Born to wealthy Argeş landowners in Piteşti, the state of Wallachia, he entered the Wallachian Army in 1838, and in 1841 started studying in Paris. Returning to his native land, Brătianu took part, with his friend C.A. Rosetti and other young politicians (including his brother), in the 1848 Wallachian Revolution, and acted as prefect of police in the provisional government formed in that year. The restoration of Imperial Russian and Ottoman authority shortly afterwards drove him into exile. He took refuge to Paris, and endeavoured to influence French opinion in favour of the proposed union and autonomy of the Danubian Principalities. In 1854, however, he was sentenced to a fine and three months' imprisonment for sedition, and later confined in a lunatic asylum; in 1856, he returned to Wallachia with his brother - afterwards one of his foremost political opponents.

He was in favor of the Danubian Principalities' (Wallachia and Moldavia) union, as a member of Partida Naţională. During the reign of Alexander Ioan Cuza (1859-1866), Brătianu figured prominently as one of the Liberal leaders. Opposition to the land reform united the emerging Liberals and Conservatives against the Domnitor and his inner circle. Both parties comprised mainly landowners, and allied to block legislation in the Chamber - causing Cuza to impose his authoritarian government in May 1864. The two-party coalition, remembered as The monstrous coalition, opted for the removal of Cuza. Brătianu took part in the deposition of 1866 and in the subsequent election of Prince Carol of Hohenzollern-Sigmaringen, under whom he held several ministerial appointments throughout the next four years.

Nonetheless, his very sinuous relationship with the new Prince was the source of several crisis situations. Notably, Brătianu would point to the benefits of a Republican project (which the Rosetti and his left wing of the Liberal Party had never ceased advocating). Thus, when the experimental Republic of Ploieşti was created in 1870 around a Liberal group, Ion Brătianu was arrested as the inspirational  figure, but was soon released. In 1871, the Liberals organized protests in favor of France - just defeated in the Franco-Prussian War - and implicitly against the German Empire, the Conservatives, and Prince Carol himself. The weight of the moment showed the weaknesses of the Liberals, as well as Carol's resolution: the Prince called on Lascăr Catargiu to form a stable and reliable government. The change in tactics forced the Liberals to form their loose tendency as a real Party in 1875. Alongside several liberal tenets, the new formation took a further step towards advocating protectionism and persecution of Jewish Romanians. In 1876, aided by C.A. Rosetti, Brătianu formed a Liberal cabinet, which remained in power until 1888 - this marked his coming to terms with Carol.

The government took steps at taking the country out of its Ottoman vassalage; however, it differed from Conservatives in that they saw the main threat posed to Romania in Austria-Hungary. Liberals were of the generation that had truly brought Romanians in Transylvania to the country's attention; on the other hand, Catargiu had signed an agreement with the Austrian Monarchy that awarded it commercial privilege in Romania – while quieting its suspicion towards Romanian irredentism. Brătianu’s government did not disturb this climate after the Russian alliance proved unsatisfactory, and the two parties resorted to assisting Romanian cultural ventures in Transylvania (until World War I). He aligned the country with Russia as soon as the Russo-Turkish War of 1877-1878 began – with its chapter, the Romanian War of Independence. While Romania did emancipate itself from Ottoman tutelage, Brătianu had to accommodate a prolonged Russian occupation, and the Congress of Berlin saw Russia seizing counties of the Budjak that were still Romanian-owned (Romania was awarded Northern Dobruja in return). In 1881, the country proclaimed itself a Kingdom. The Congress also pressured the Liberals to discard the discrimination policies, and the government agreed to allow Jews and Dobrujan Muslims to apply for citizenship (with a 10-year probation), but continued forbidding foreign-born people or non-citizens from owning land.

The Brătianu government introduced most modern reforms in the administrative, educational, economical, and military fields. It celebrated its main success in 1883, when the Liberals managed to have the 1866 Constitution of Romania amended – enlarging the number of electors and establishing a third electoral college, one that gave some representation to peasants and the urban employees. The move was not radical, and it served to obtain the Liberals political ascendancy: the very first elections under the new law brought them an overwhelming majority. After 1883 Brătianu acted as sole leader of the party, owing to a quarrel with Rosetti, his friend and political ally for nearly forty years. His long tenure of office, without parallel in Romanian history, rendered Brătianu extremely unpopular, and at its close his impeachment appeared inevitable. But any proceedings taken against the minister would have involved charges against the king, who was largely responsible for his policy, and the impeachment was averted by a vote of parliament in February 1890.

Besides being the leading statesman of Romania during the critical years 1876-1888, he attained some eminence as a writer. His French language political pamphlets, Mémoire sur l'empire d'Autriche dans la question d'Orient ("Account of the Austrian Empire in the Oriental Issue", 1855), Réflexions sur la situation ("Musings on the Situation", 1856), Mémoire sur la situation de la Moldavie depuis le traité de Paris ("Account on Moldavia's Situation After the Treaty of Paris", 1857), and La Question religieuse en Roumanie ("The Religious Issue in Romania", 1866), were all published in Paris.