In 1792, he was sent twice, though not officially, to Britain to avert war. Besides an initial declaration of neutrality during the first campaigns of 1792, his mission ultimately failed. In September 1792, he left Paris for England just at the beginning of September Massacres, yet declined émigré status. Because of incriminating papers found in the armoire de fer, the National Convention issued a warrant for his arrest in December 1792. His stay in England was not uneventful either; in March 1794, he was forced to leave the country by Pitt's expulsion order. He then arrived in the United States where he stayed until his return to France in 1796. During his stay, he supported himself by working as a bank agent, involved in commodity trading and real estate speculation. He was the house guest of Senator Aaron Burr of New York. Talleyrand years later refused the same generosity to Burr because Talleyrand had been friends with Alexander Hamilton, whom Burr had killed in a duel. Talleyrand is also reputed to have stayed at the Wilson House in Oyster Bay, New York.

After 9 Thermidor, he mobilised his friends (most notably the abbé Martial Borye Desrenaudes and Germaine de Staël) to lobby in the National Convention and then the newly established Directoire for his return. His name was then suppressed from the émigré list and he returned to France on 25 September 1796. In 1797, he became Foreign Minister. He was implicated in the XYZ Affair which escalated the Quasi-War with America. Talleyrand saw a possible political career for Napoleon during the Italian campaigns of 1796 to 1797. He wrote many letters to Napoleon and the two became close allies. Talleyrand was against the destruction of the Republic of Venice, but he complimented Napoleon when peace with Austria was concluded (Venice was given to Austria), probably because he wanted to reinforce his alliance with Napoleon.

Together with Napoleon's younger brother, Lucien Bonaparte, he was instrumental in the 1799 coup d'état of 18 Brumaire, establishing the French Consulate government. Soon after he was made Foreign Minister by Napoleon, although he rarely agreed with Napoleon's foreign policy. The Pope also released him from the ban of excommunication in the Concordat of 1801, which also revoked the Civil Constitution of the Clergy. Talleyrand was instrumental in the completion of the Treaty of Amiens in 1803.

In March 1804, he may have been involved in the kidnapping and execution of the Duke of Enghien, which was a cause célèbre in Europe, as an echo of the execution of Louis XVI: a charge made later by François-René de Chateaubriand. Talleyrand advocated against violence, most notably speaking out against the guillotine, and during the coup of 18 Brumaire he ensured that Barras could leave Paris safely. Talleyrand was also an integral player in the German Mediatisation, or Reichsdeputationshauptschluss. While the Treaty of Campo Formio had, on paper, stripped German princes of their lands beyond the left bank of the Rhine, it was not until the Treaty of Lunéville that this was enforced. The French annexed these lands and it was deemed proper that the deposed sovereigns receive new territories on the Right Bank of the Rhine. As many of these rulers gave out bribes in order to secure new lands Talleyrand became quite wealthy. He gained an estimated 10 million francs in the process. This was the first blow in the destruction of the Holy Roman Empire.

Napoleon forced his hand into marriage in September 1802 to longtime mistress Catherine Grand (née Worlée). Talleyrand purchased the Château de Valençay in May 1803, upon the urging of Napoleon. This would later be the site of the imprisonment of the Spanish Royalty after Napoleon's invasion from 1808 - 1813.

In May 1804, Napoleon bestowed upon him the title of Grand Chamberlain of the Empire. In 1806, he was made Sovereign Prince of Benevento (or Bénévent). Talleyrand was opposed to the harsh treatment of Austria in the 1805 Treaty of Pressburg and of Prussia in the Peace of Tilsit in 1807. In 1806, after Pressburg and just like in 1803, he profited greatly from the reorganization of the German lands, this time into the Confederation of the Rhine. He was then shut out completely from the negotiations at Tilsit. Afterward her famous failed imploring of Napoleon to spare her nation, the Queen Louise of Prussia wept and was consoled by Talleyrand. This gave him a good name among the elites of the European countries outside France. He resigned as minister of foreign affairs in 1807, because of a myriad of suggested reasons, some genuine and others not. In essence, he traded his position as minister for the imperial title of Vice Grand Elector. The ill-fated Peninsula War, initiated in 1808, was the breaking point for Talleyrand concerning his loyalty to the Emperor.

His actions at the Congress of Erfurt, in September – October 1808, helped to thwart Napoleon's plans. It was here that he counseled Tsar Alexander nightly on how to deal with Napoleon. The Tsar's attitude towards Napoleon was one of apprehensive opposition. Talleyrand repaired the confidence of the Russian monarch and together they rebuked Napoleon's attempts to form a direct anti-Austrian military alliance. Of course, this was not why Talleyrand had been brought to the conference. In fact, Napoleon had expected him to help convince the Tsar to accept all of his proposals, yet, somehow he never discovered the acts of treason committed by Talleyrand in Erfurt.

After his resignation in 1807 from the ministry, Talleyrand began to accept bribes from hostile countries, particularly Austria and Russia to betray Napoleon's secrets. Talleyrand and Fouché, who were typically enemies in both politics and the salons, had a rapprochement in late 1808 and entered into discussions over the imperial line of succession. Napoleon had yet to address this matter and the two men knew that without a legitimate heir France would crumble into chaos in the wake of Napoleon's possible death. Even Talleyrand, who believed that Napoleon's policies were leading France to ruin, understood the necessity of peaceful transitions of power. However, Napoleon received word of their actions and deemed them treasonous. This perception caused the famous dressing down of Talleyrand in front of Napoleon's marshals, during which Napoleon famously claimed that he could "break him like a glass, but it's not worth the trouble" and added with a scatological tone that Talleyrand was "shit in a silk stocking", to which the minister coldly retorted, once Napoleon had left, "Pity that so great a man should have been so badly brought up!"

Talleyrand spent the last few years of the empire working as an informant for Austria and (sometimes) Russia. He opposed the further harsh treatment of Austria in 1809 after the War of the Fifth Coalition, also known as the War of 1809. He was also a critic of the French invasion of Russia in 1812. He was offered to resume his role in late 1813 but Talleyrand adeptly understood that Napoleon was nearing his end. On April 1, 1814 he led the French Senate in establishing a provisional government in Paris, of which he was elected president. On April 2 the Senate officially deposed Napoleon and by April 11 had created the Treaty of Fontainebleau and a new constitution to re-establish the Bourbons as monarchs of France.

When Napoleon was succeeded by Louis XVIII in April 1814, Talleyrand was one of the key agents of the restoration of the House of Bourbon, while opposing the new legislation of Louis's rule. Talleyrand was the chief French negotiator at the Congress of Vienna, and, in that same year, he signed the Treaty of Paris. It was due in part to his skills that the terms of the treaty were remarkably lenient towards France. As the Congress opened, the right to make decisions was restricted to four countries: Austria, the United Kingdom, Prussia, and Russia. France and other European countries were invited to attend, but were not allowed to influence the process. Talleyrand promptly became the champion of the small countries and demanded admission into the ranks of the decision making process. The four powers admitted France and Spain to the decision making backrooms of the conference after a good deal of diplomatic maneuvering by Talleyrand, who had the support of the Spanish representative, Pedro Gómez Labrador, Marquis of Labrador. Spain was excluded after a while (a result of both the Marquis of Labrador's incompetence as well as the quixotic nature of Spain's agenda), but France (Talleyrand) was allowed to participate until the end. Russia and Prussia sought to enlarge their territory at the Congress. Russia demanded annexation of Poland (already occupied by Russian troops), and this demand was finally satisfied, despite protests by France, Austria and the United Kingdom. Austria was afraid of future conflicts with Russia or Prussia and the United Kingdom was opposed to their expansion as well - and Talleyrand managed to take advantage of these contradictions between the former anti-French coalition. On 3 January 1815, a secret treaty was signed by France's Talleyrand, Austria's Metternich and Britain's Castlereagh. By this tract, officially a secret treaty of defensive alliance, the three powers agreed to use force if necessary to "repulse aggression" (of Russia and Prussia) and to protect the "state of security and independence". This agreement effectively spelled the end of the anti-France coalition.

Talleyrand, having managed to establish a middle position, received some favours from the other countries in exchange for his support: France returned to its 1792 boundaries without reparations, with French control over papal Avignon, Montbéliard (Mompelgard) and Salm, which had been independent at the start of the French Revolution in 1789. It would later be debated which outcome would have been better for France: allowing Prussia to annex all of Saxony (Talleyrand ensured that only part of the kingdom would be annexed) or the Rhine provinces. The first option would have kept Prussia farther away from France, but would have needed much more opposition as well. Some historians have argued that Talleyrand's diplomacy wound up establishing the faultlines of World War I, especially as it allowed Prussia to engulf small German states west of the Rhine. This simultaneously placed Prussian armed forces at the French - German frontier, for the first time; made Prussia the largest German power in terms of territory, population and the industry of the Ruhr and Rhineland; and eventually helped pave the way to German unification under the Prussian throne. However, at the time Talleyrand's diplomacy was regarded as successful, as it removed the threat of France being partitioned by the victors. Talleyrand also managed to strengthen his own position in France (ultraroyalists had disapproved of the presence of a former "revolutionary" and "murderer of the Duke d'Enghien" in the royal cabinet).

Napoleon's return to France in 1815 and his subsequent defeat, the Hundred Days, was a reverse for the diplomatic victories of Talleyrand; the second peace settlement was markedly less lenient and it was fortunate for France that the business of the Congress had been concluded. Talleyrand resigned in September of that year, either over the second treaty or under pressure from opponents in France. For the next fifteen years he restricted himself to the role of "elder statesman", criticising — and intriguing — from the sidelines. However, when King Louis-Philippe came to power in the July Revolution of 1830, Talleyrand agreed to become ambassador to the United Kingdom, a post he held from 1830 to 1834. In this role, he strove to reinforce the legitimacy of Louis-Philippe's regime, and proposed a partition plan for the newly independent Belgium.

Talleyrand had a reputation as a voluptuary and a womaniser. He left no legitimate children, though he is believed to have fathered illegitimate children. Four possible children of his have been identified: Charles Joseph, comte de Flahaut, generally accepted to be an illegitimate son of Talleyrand; the painter Eugène Delacroix, once rumored to be Talleyrand's son, though this is doubted by historians who have examined the issue (for example, Léon Noël, French ambassador); the "Mysterious Charlotte", possibly his daughter by his future wife, Catherine Worlée Grand; and Pauline, ostensibly the daughter of the Duc and Duchess Dino. Of these four, only the first is given credence by historians.

Aristocratic women were a key component of Talleyrand's political tactics, both for their influence and their ability to cross borders unhindered. His presumed lover Germaine de Staël was a major influence on him, and he on her. Though their personal philosophies were most different, (she, a romantic; he, very much a baroque sensibility), she assisted him greatly, most notably by lobbying Barras to permit Talleyrand to return to France from his American exile, and then to have him made foreign minister. He lived with Catherine Worlée, born in India and married there to Charles Grand. She had traveled about before settling in Paris, as a notorious courtesan in the 1780s, for several years before she divorced Grand and married Talleyrand in 1802. Talleyrand, largely indifferent, tried to prevent the marriage, but after repeated postponements, was obliged by Napoleon to carry it out to preserve his political career. Rumors about her stupidity, though unfounded, continue to circulate to this day.

Talleyrand's venality was celebrated; in the tradition of the ancien régime, he expected to be paid for the state duties he performed — whether these can properly be called "bribes" is open to debate. For example, during the German Mediatisation, the consolidation of the small German states, a number of German rulers and elites paid him to save their possessions or enlarge their territories. Less successfully, he solicited payments from the United States government to open negotiations, precipitating a diplomatic disaster (the "XYZ Affair"). The difference between his diplomatic success in Europe and failure with the United States illustrates his capacities and limitations — his manners, behavior, and tactics made sense in the context of the Old World, but were perceived as antiquated and corrupt by the more idealistic Americans. After Napoleon's defeat, he ceased using his imperial title "Prince of Benevento", referring to himself henceforth as the "Prince de Talleyrand", in the same manner as his estranged wife.

Talleyrand was a great conversationalist, gourmet, and wine connoisseur. From 1801 to 1804, he owned Château Haut-Brion in Bordeaux. He employed the renowned French chef Carême, one of the first celebrity chefs known as the "chef of kings and king of chefs", and was said to have spent an hour every day with him. His Paris residence on the Place de la Concorde, acquired in 1812 and sold to James Mayer de Rothschild in 1838, is now owned by the Embassy of the United States.

Near the end of his life, Talleyrand became interested in Catholicism again while teaching his young granddaughter simple prayers. The Abbé Félix Dupanloup came to Talleyrand in his last hours, and according to his account Talleyrand made confession and received extreme unction. When the abbé tried to anoint Talleyrand's palms, as prescribed by the rite, he turned his hands over to make the priest anoint him on the back of the hands, since he was a bishop. He also signed, in the abbé's presence, a solemn declaration in which he openly disavowed "the great errors which . . . had troubled and afflicted the Catholic, Apostolic and Roman Church, and in which he himself had had the misfortune to fall." Many, however, have doubted the sincerity of the conversion given Talleyrand's history. He died on 17 May 1838 and was buried at his Château de Valençay. Today, when speaking of the art of diplomacy, the phrase "he is a Talleyrand" is used to denote a statesman of great resource and skill.