He was born in Paris, of a Limousin family traceable back to the 15th century. After a brilliant career as a student, he entered the Church, this being the best way to attain a distinguished position. In 1751 he became a doctor of theology, though there were doubts as to the orthodoxy of his thesis. In 1752 he was appointed grand vicar to the Archbishop of Rouen. After visiting Rome, he was made Bishop of Condom (1760), and in 1763 was translated to the archbishopric of Toulouse. His many famous friends included A. R. J. Turgot, André Morellet and Voltaire, and in 1770 he was elected to the Académie française. He was three times head of the bureau de jurisdiction at the general assembly of the clergy. He also took an interest in political and social questions of the day, and addressed to Turgot a number of memoires on these subjects, one of them, treating of pauperism, being especially remarkable.
In 1787 he was nominated as president of the Assembly of Notables, in which capacity he attacked the fiscal policy of Calonne, whom he succeeded as head of the conseil des finances (finance minister) on April 1787. Once in power, he succeeded in making the parlement register edicts dealing with internal free trade, the establishment of provincial assemblies and the redemption of the corvée. When the parlement refused to register edicts on the stamp duty and the proposed new general land-tax, he persuaded Louis XVI to hold a lit de justice, to enforce their registration. To crush the opposition to these measures, he persuaded Louis to exile the parlement to Troyes (18 August 1787). When the parlement agreed to prolong the direct tax on all kinds of income, he recalled the councillors to Paris. A further attempt to force the parlement to register an edict for raising a loan of 120 million livres met with determined opposition. The struggle of the parlement against the incapacity of Brienne ended on 8 May in its consenting to an edict for its own abolition, with the proviso that the Estates-General should be summoned to remedy the disorders of the state. He resigned as finance minister on 25 August 1788.
Brienne, who had in the meantime been made Archbishop of Sens, now faced almost universal opposition. He was forced to suspend the Cour plenière which had been set up to take the place of the parlement, and to promise that the States-General should be summoned. Even these concessions were not enough to keep him in power, and on 29 August he had to retire, leaving the treasury empty. On 15 December following, he was made a cardinal, and went to Italy, where he spent two years. After the outbreak of the French Revolution he returned to France, and took the oath of the Civil Constitution of the Clergy in 1790. He was repudiated by Pope Pius VI, and in 1791 had to give up the biretta. He was also one of the few prelates of the old regime to swear the civic oath required by the revolutionary civil constitution.
He retired to an abbey confiscated in the Revolution. He repudiated Catholicism in 1793, at the height of the French Revolution.
Both his past and present conduct made him an object of suspicion to the revolutionaries; he was arrested at Sens on 9 November 1793, and died in prison, either of an apoplectic stroke or by poison.