Delcassé was a journalist who vigorously supported the moderate republican programs of Léon Gambetta and the colonial expansionist policies of Jules Ferry. Delcassé was elected to the Chamber of Deputies in 1885; in 1893 he joined Alexandre Ribot's Cabinet as under secretary of commerce, industry, and colonies and in 1894–95 served as minister of colonies. In 1898 he was given the post of foreign minister in the government of Henri Brisson. He remained in charge of foreign affairs in six successive governments, a seven-year tenure unprecedented in the Third Republic.

Fearing the Triple Alliance of Germany, Italy, and Austria-Hungary, Delcassé concluded that France's best interest lay in a continuing friendship with Russia and a new understanding with Britain. In 1904 he reached agreement with the British on a broad range of questions, establishing the basis for the Anglo-French Entente Cordiale (April 8, 1904), which remained a factor in European affairs until 1940. At the same time he paved the way for the Anglo-Russian agreement of 1907, thus bringing the three powers together in the Triple Entente that was to be the nucleus of the Allied coalition in World War I.

Opposition to his policies by Prime Minister Maurice Rouvier led to Delcassé's resignation in 1905, but because his downfall was attributed to German influence, it was followed by an anti-German reaction in France, and the ties he had forged were strengthened. Delcassé returned to prominence in 1909 as chairman of a commission appointed to investigate French naval weakness. As minister of marine (1911–13), he arranged for cooperation between the British and French fleets in case of war; this arrangement was a crucial factor in leading Britain to declare war against Germany in support of France when World War I began. During the war he served as foreign minister in the government of René Viviani until his retirement in 1915.