In 1800 Poinsett returned to Charleston hoping to pursue a military career. His father did not want his son to be a soldier. Hoping to entice his son to settle into the Charleston aristocracy, Dr. Poinsett had his son study law under H.W. DeSaussure, a prominent lawyer of Charleston. Poinsett was not interested in becoming a lawyer, and convinced his parents to allow him to go on an extended tour of Europe in 1801. DeSaussure sent with him a list of law books including Blackstone's Commentaries and Burn’s Ecclesiastical Law, just in case young Poinsett changed his mind regarding the practice of law.

Beginning in 1801, Poinsett traveled the European continent. In the spring of 1802, Poinsett left France for Italy traveling through the Alps and Switzerland. He visited the cities of Naples and hiked up Mount Etna on the island of Sicily. In the spring of 1803 he arrived in Switzerland and stayed at the home of Jacques Necker and his daughter, Madame de Stael. Necker, French Finance Minister from 1776 to 1781 under Louis XVI, had been driven into exile by Napoleon. On one occasion, Robert Livingston, the United States minister to France, was invited for a visit while he was touring Savoy, France, and Switzerland. Poinsett was compelled to assume the role of interpreter between the deaf Livingston and the aged Necker whose lack of teeth made his speech almost incomprehensible. Fortunately, Madame de Stael tactfully assumed the duty of translation for her elderly father.

In October 1803, Poinsett left Switzerland for Vienna, Austria, and from there journeyed to Munich. In December he received word that his father was dead, and that his sister, Susan, was seriously ill. He immediately secured passage back to Charleston. Poinsett arrived in Charleston early in 1804, months after his father had been laid to rest. Hoping to save his sister’s life, Poinsett took her on a voyage to New York, remembering how his earlier voyage to Lisbon had intensified his recovery. Yet, upon arriving in New York City, Susan Poinsett died. As the sole remaining heir, Poinsett inherited a small fortune in town houses and lots, plantations, bank stock, and “English funds.” The entire Poinsett estate was valued at a hundred thousand dollars or more.

Poinsett arrived in the Russian capital of St. Petersburg in November 1806. Levett Harris, consul of the United States at St. Petersburg, and the highest American official in the country, hoped to introduce Poinsett at court to Czar Alexander. Learning that Poinsett was from South Carolina, the Empress asked him if he would inspect the cotton factories under her patronage. Poinsett and Consul Harris traveled by sleigh to Cronstadt to see the factories. Poinsett made some suggestions on improvement, which the Empress mother accepted. Poinsett did not believe the cotton industry could be successful in Russia because of the necessity of employing serfs who received no compensation and therefore could have no interest in its prosperity. Furthermore, he believed that the institution of serfdom made it difficult for Russia to have a merchant marine or become industrialized.

In January, 1807, Czar Alexander and Poinsett dined at the Palace. Czar Alexander attempted to entice Poinsett into the Russian civil or military service. Poinsett was hesitant, which prompted Alexander to advise him to “see the Empire, acquire the language, study the people,” and then decide. Always interested in travel, Poinsett accepted the invitation and left St. Petersburg in March 1807 on a journey through southern Russia. He was accompanied by his English friend Lord Royston and eight others.

With letters recommending them to the special care of all Russian officials, Poinsett and Royston made their way to Moscow. They were among the last westerners to see Moscow before its burning in October 1812 by Napoleon’s forces. From Moscow they traveled to the Volga River, and then by boat to Astrakhan, situated at the mouth of the river. Poinsett's company now entered the Caucusus, containing a very diverse population, and only recently acquired by Russia through conquests by Czars Peter the Great and Catherine the Great. Because of ethnic conflict, the area was extremely dangerous. They were provided with a Cossack escort as they traveled between Tarki and Derbent, but when a Tartar dignitary claimed that this would only provoke danger, the escort was bypassed for the security of the Tartar chiefs. This new security increased the numbers in Poinsett’s company, which they believed made it less vulnerable to attack as it passed out of Russia proper. Thus, they were joined by a Persian merchant, who was transporting young girls he had acquired in Circassia to Baku and harems in Turkey. With a strong Persian and Kopak guard, the party left Derbent and entered the realm of the Khan of Kuban.

While traveling through the Khanate, a tribal chief stole some of the horses in Poinsett’s party. Poinsett boldly decided to go out of his way to the court of the Khan in the town of Kuban to demand their return. As there were normally never any foreigners in this place, the Khan was surprised. Of course, he had never heard of the United States, and Poinsett did the best he could to answer all the questions the Khan had. In order to convey the greatness of the U.S., Poinsett spoke at length on its geography. The Khan referred to President Thomas Jefferson as the Shah of America. Finally, Poinsett stated that the theft of his horses would reflect badly on the fair name of the Khanate. The Khan was impressed and told Poinsett that the head of the guilty chief was his for the asking, yet since the thief had made it possible for him to accept such a distinguished visitor, perhaps a pardon might be in order. Poinsett's company traveled to Baku on the Caspian Sea. He noted that because of the petroleum pits in the region, it had long been a spot of pilgrimage for fire worshipers. He became one of the earliest U.S. travelers to the Middle East, where, in 1806, the Persian khan showed him a pool of petroleum, which he speculated might someday be used for fuel.

Attracted by the military movements in the Caucasus Mountains, Poinsett visited Erevan, which was then besieged by the Russian Army. After a time with the troops, Poinsett and company journeyed through the mountains of Armenia to the Black Sea. Avoiding Constantinople because of conflict between Russia and the Ottoman Empire, the party proceeded to the Crimea, then through Ukraine, reaching Moscow late in 1807. The trip had been hazardous and Poinsett’s health was much impaired. Furthermore, of the nine who had set out on the journey the previous March, Poinsett and two others were the only survivors. Upon his return to Moscow, Czar Alexander’s discussed the details of Poinsett’s trip with him and offered him a colonelcy in the Russian Army. However, news had reached Russia of the attack of the H.M.S. Leopard upon the Chesapeake and war between the United States and Great Britain seemed certain. Poinsett eagerly sought to return to his homeland. Before leaving Russia, Poinsett met one last time with Czar Alexander, who expressed his approval of the energetic measures by the Congress of the United States to resist the maritime pretensions of Britain. The Czar declared that Russia and the United States should maintain the same policy of respect. Poinsett again met with Foreign Minister Count Romanzoff where the Russian disclosed to Poinsett that the Czar ardently desired to have a minister from the United States at the Russian Court.

He served as a "special agent" to two South American countries from 1810 to 1814, Chile and Argentina. President James Madison appointed him in 1809 as Consul in General. Poinsett was to investigate the prospects of the revolutionists, in their struggle for independence from Spain. On December 29, 1811, he reached Santiago. The Larrain and Carrera families were jockying for power in Chile. By the time Poinsett arrived, the Carreras gained control under its leader, Jose Miguel Carrera. Carrera’s government was split on how to receive Poinsett. The tribunal del consulado, the organization with jurisdiction over commercial matters opposed his reception on the grounds that his nomination had not been confirmed by the U.S. Senate. Moreover, many of the members of this group were royalists, hoping for closer relations with Spain or Britain. Nevertheless, Poinsett received recognition as a majority wanted to establish trade relations with the U.S.

The official reception finally occurred on February 24, 1812. Poinsett was the first accredited agent of a foreign government to reach Chile. Poinsett’s main adversary in Chile was the junta of Peru. The Colonial Viceroy of Peru resented the Chileans’ disregard for Spanish authority. He declared the laws of the new Chilean government relative to free commerce null and void and sent privateers to enforce the old colonial system. Seizure of ships and confiscation of cargoes followed, to the dismay of foreign traders, especially Americans. Poinsett learned of the seizure of an American whaler searching for supplies from an intercepted letter from the governor of San Carlos de Chiloe to the viceroy of Lima. Furthermore, he received intelligence that ten other American vessels were seized at Talcahuana in the Bay of Conception. With little guidance from the Madison administration, Poinsett decided that something had to be done to halt violations of American neutral rights.

Poinsett urged Chile to close its ports to Peru, but the authorities in Santiago did not feel they were strong enough to take such a step. Instead they urged Poinsett to aid them in obtaining arms and supplies from the United States. Although Poinsett furnished the names of certain dealers, many of them were already too involved with the conflict between the U.S. and Britain to give any attention to the Chileans. During this time Poinsett also urged the Chileans to create a national constitution. A commission consisting of Camilo Henriquez and six others was named for the purpose of drawing up a constitution. The first meeting of the group was held at Poinestt’s residence on July 11, 1812.

The seizure of American ships by royalist Peru continued. Poinsett's commission stated that he was to protect all American property and provide for American citizens. After a consultation with Carrera, Poinsett accepted a commission into the Chilean army to fight against the Spanish Royalists based in Peru. Poinsett was later given the rank of general in Carrera’s army. He led a charge at the head of the Chilean cavalry in the Battle of San Carlos and secured a victory for Chile. From there, he went with a battery of flying artillery to the Bay of Conception, where ten American vessels had been seized. He arrived at dark near the seaport of Talcahuano, and began firing on the town. At dawn he sent an emissary to demand the surrender of the bay to the Junta of Chile. The Peruvian royalists surrendered on May 29, 1813.

In early September 1813, the United States Frigate Essex arrived in Chilean waters and cleared them of English whalers and cruisers. When Commodore David Porter of the U.S.S. Essex arrived in Santiago, Poinsett received the first authoritative news of the War of 1812. He now desired more than ever to return to his home. However, this could not happen until Commodore Porter completed his cruise of the Pacific. Finally, as the Essex set out with Poinsett aboard, the Phoebe and Cherub, British warships were spotted in the port of Valparaiso. Commodore Porter returned to Santiago to utilize the guns of the fort there. He also hoped the neutrality of the bay would discourage any British attack. Captain Hillyer attacked nonetheless, and Commodore Porter was defeated. The British decided to send their American prisoners back to the U.S. in a cartel. Poinsett was forced to stay behind in Chile.

When Poinsett returned to Buenos Aires, he found a Junta that was very well established with a strong British influence. He managed to negotiate a commercial agreement with the Junta by which American articles of general consumption were admitted free of duty. As American shipping had been driven from the South Atlantic, it took some time to find passage back to the United States. Poinsett finally secured passage aboard a vessel going to the Bahia, a state in the northeastern part of Brazil. From there he transferred to another ship bound for the Madeira Islands, located 535 miles from mainland Europe. Poinsett finally reached Charleston on May 28, 1815.

Returning to Charleston in 1815, Poinsett spent the first few months putting his personal affairs in order. From now until 1825, Poinsett stayed in South Carolina seeking to build a reputation in his home state, and hold office. Yet, he became to be respected as an authority on Latin American affairs. In 1816 Poinsett received a letter from his old friend General Jose Miguel Carrera. Since Poinsett’s departure, the Chilean Royalists had consolidated their hold on Chile, and after spending a year in exile in the provinces of the Rio de la Plata (Argentina), Carrera came to the United States in January 1816 to stimulate interest for a revolution in Chile. Poinsett wrote Carrera back stating that he intended to urge the U.S. government to develop decisive policy regarding the Spanish colonies. President James Madison received General Carrera warmly, but never offered him any official encouragement because he worried that seriously entertaining Carrera might jeopardize gaining Florida. Carrera’s only hope of help came from his former comrade.

In July 1816, Poinsett traveled to New York to meet Carrera. While there, Poinsett attempted to interest John Jacob Astor, the wealthy owner of the American Fur Company, in supplying Carrera’s Chilean revolutionists with weapons; however, Astor declined to get involved. In August 1816, Poinsett was able to arrange some conferences in Philadelphia between the Chilean leader and some of Napoleon’s former officers. Among them were Marshal Emanuel Grouchy, who had commanded Napoleon’s body guards during the Russian Campaign. Poinsett also arranged a meeting between Carrera and General Bertrand Count Clauzel. Clauzel had distinguished himself in the Napoleonic Wars and was given the distinction of Peer of France by Napoleon in 1815. Although Carrera’s movement never benefited from the experience of these French officers, Poinsett did succeed in obtaining contracts with the firm D’Arcy and Didier of Philadelphia to supply arms for the expedition which Carrera was planning.

On August 29, 1816, Poinsett set out on a tour of the U.S. along with four men and one slave from Charleston, set out from Philadelphia on a tour of the West. They made stops in Pittsburgh and Cincinnati, before stopping in Lexington, Kentucky. While in Lexington, the group stayed with Congressman Henry Clay. It is possible that in relating his experiences in Chile, Poinsett may have made quite an impression on Clay, who would distinguish himself as the biggest American supporter for Spanish American independence in the next few years. From Lexington, the travelers made their way to Louisville, and then on to Nashville, Tennessee. While in Nashville, Poinsett and his companions had breakfast with Andrew Jackson. Poinsett, after traversing more than two thousand miles, finally returned to Charleston in early November 1816.

Poinsett was aware that his friends had nominated him to represent Charleston, South Carolina in the state legislature. In Greenville on his way back home, he learned that he had won the nomination and had a seat in the state house of representatives. As he was beginning his first term in April 1817, the rumored position of American envoy to South America became reality. On April 25, 1817, acting Secretary of State Robert Rush offered Poinsett the position of special commissioner to South America stating, “No one has better qualifications for this trust than yourself.” Rush also added that he would be personally gratified by Poinsett’s acceptance. Nevertheless, Poinsett declined the honor. In May Poinsett explained to President Monroe that he had recently accepted a seat in the legislature of South Carolina and could not resign it “without some more important motive than this commission presents.” Poinsett perceived that the mission would not lead to any substantial decision for recognition and was unwilling to give up his seat in the House. In the same letter, Poinsett offered his knowledge of South America to the service of whomever the Monroe administration appointed.

Poinsett’s political values mirrored those of others at the time who considered themselves Jeffersonian Republicans. One of the most important measures supported by Jeffersonian Republicans following the War of 1812 was that of federally funded internal improvements. As a member of the state legislature, this was one of Poinsett’s passions. After being re-elected to the South Carolina House in 1818, he became a member of the Committee on Internal Improvements and Waterways.

Poinsett also served on the South Carolina Board of Public Works as President. One of the main plans of this board was to link the interior of the state with the seaboard. Another important project was the construction of a highway from Charleston through Columbia, to the northwestern border of South Carolina. It was designed to promote interstate commerce as well as to draw commerce from eastern Tennessee and western North Carolina to Charleston. Poinsett, a seasoned traveler, knew better than anyone the importance of good roadways. Through his journeys in New England in 1804 and especially to the west in 1816, Poinsett understood that his country could benefit from transportation facilities. In 1820, Poinsett won a seat in the United States House of Representatives for the Charleston district. As a congressman, Poinsett continued to call for internal improvements, but he also advocated the maintenance of a strong army and navy. In December 1823, Poinsett submitted a resolution calling upon the Committee on Naval Affairs to inquire into the expediency of authorizing the construction of ten additional sloops of war. As a member of the Committee on Foreign Affairs, Poinsett took strong views on developments in South America. Poinsett’s political views were aligned with such nationalists as Secretary of State John Quincy Adams and Secretary of War John C. Calhoun. Poinsett, like many opponents of Clay's American system, opposed the Tariff of 1824.

He simultaneously served as a special envoy to Mexico from 1822 to 1823 and was appointed the first American minister to Mexico in 1825, and became embroiled in the country’s political turmoil until his recall in 1830. It was during this time that he visited the area of southern Mexico called Taxco del Alarcon were he found what was later to become known in the united states as the poinsettia, in Mexico is called "Flor de Noche Buena" (Christmas Eve flower). (The Aztecs referred to the winter blooming plant as cuetlaxochitl; its Latin name is Euphorbia pulcherrima or "the most beautiful Euphorbia.") Poinsett, an avid amateur botanist, sent samples of the plant home to the States and by 1836 the plant was most widely known as the "poinsettia."

In 1830, Poinsett returned to South Carolina to espouse the Unionist cause in nullification quarrels and to again serve in the South Carolina state legislature, from 1830 to 1831. In this capacity, Poinsett was President Andrew Jackson's confidential agent. Between October 1832, and March 1833, his correspondence kept Jackson abreast of the evolving situation in their home state, helping Jackson to craft policy in regards to the crisis. He was occupied thus until 1833, when he married Mary Izard Pringle.

Poinsett served as Secretary of War from March 7, 1837 to March 5, 1841 and presided over the continuing removal of Indians west of the Mississippi and over the Seminole War; reduced the fragmentation of the Army by concentrating elements at central locations; equipped the light batteries of artillery regiments as authorized by the 1821 army organization act; and again retired to his plantation at Georgetown, South Carolina, in 1841.

During the 1820s, Poinsett was a member of the prestigious society, Columbian Institute for the Promotion of Arts and Sciences, who counted among their members former presidents Andrew Jackson and John Quincy Adams and many prominent men of the day, including well known representatives of the military, government service, medical and other professions.

He was a cofounder of the National Institute for the Promotion of Science and the Useful Arts in 1840, a group of politicians advocating for the use of the "Smithson bequest" for a national museum that would showcase relics of the country and its leaders, celebrate American technology and document the national resources of North America. The group was defeated in its efforts, as other groups wanted scientists, rather than political leaders, guiding the fortunes of what would become the Smithsonian Institution.

He died near Stateburg, South Carolina, in 1851 and is buried at the Church of the Holy Cross Episcopal Cemetery.