From the beginning of his career in the Chamber of Deputies, Briand was occupied with the question of the separation of church and state. He was appointed reporter of the commission charged with the preparation of the 1905 law on separation, and his masterly report at once marked him out as one of the coming leaders. He succeeded in carrying his project through with but slight modifications, and without dividing the parties upon whose support he relied. He was the principal author of the law of separation, but, not content with preparing it, he wished to apply it as well. The ministry of Maurice Rouvier was allowing disturbances during the taking of inventories of church property, a clause of the law for which Briand was not responsible. Consequently he accepted the portfolio of Public Instruction and Worship in the Sarrien ministry (1906). So far as the Chamber was concerned his success was complete. But the acceptance of a position in a bourgeois ministry led to his exclusion from the Unified Socialist Party (March 1906). As opposed to Jaurès, he contended that the Socialists should co-operate actively with the Radicals in all matters of reform, and not stand aloof to await the complete fulfillment of their ideals.

Briand succeeded Clemenceau as Prime Minister in 1909, serving until 1911, and served again for a few months in 1913. In October 1915, following on French defeats in the First World War, Briand again became Prime Minister, and, for the first time, Foreign Minister, succeeding René Viviani and Théophile Delcassé, respectively. His tenure was not particularly successful, and he resigned in March 1917 as a result of disagreements over the prospective Nivelle Offensive, to be succeeded by Alexandre Ribot.

Briand returned to power in 1921, but his efforts to come to an agreement over reparations with the Germans failed in the wake of German intransigence, and he was succeeded by the more bellicose Raymond Poincaré. In the wake of the Ruhr Crisis, however, Briand's more conciliatory style became more acceptable, and he returned to the Quai d'Orsay in 1925, remaining foreign minister until his death in 1932. Briand negotiated the Briand-Ceretti Agreement with the Vatican giving the French government a role in the appointment of Catholic bishops.

Aristide Briand received the 1926 Nobel Peace Prize together with Gustav Stresemann of Germany for the Locarno Treaties (Austen Chamberlain of the United Kingdom had won a share of the Peace Prize a year earlier for the same agreement). A 1927 proposal by Briand and United States Secretary of State Frank B. Kellogg for a universal pact outlawing war led the following year to the Pact of Paris, aka the Kellogg-Briand Pact. The cordial relations between Briand and Stresemann, the leading statesmen of their respective countries, were cut short by the unexpected death of Stresemann in 1929 and of Briand in 1932. Briand is noted as among the first to propose a union of European nations, in a speech in favor of a European Union in the League of Nations on 8 September 1929, and in 1930, he wrote his "Memorandum on the Organization of a Regime of European Federal Union" for the Government of France.