A rising conservative lawyer, known for his eloquence and mastery of legal detail, Waldeck-Rousseau was elected a deputy in 1879. In 1881 he became minister of the interior in the Cabinet of Léon Gambetta, one of the founders of the Third Republic, and he filled the same post, under Jules Ferry, from 1883 to 1885. In 1884 he sponsored the Loi Waldeck-Rousseau, which made trade unions legal, though with important restrictions. After another term as deputy (1885–89), he retired to make his fortune at the bar. In 1894, however, he became a senator.

In June 1899, when demonstrations and counterdemonstrations over the Dreyfus Affair threatened public order, Waldeck-Rousseau was asked to form a “government of republican defense.” His Cabinet was based on pro-Dreyfus moderates but included members of both the right and the left, such as Alexandre Millerand, the first Socialist to hold Cabinet office. When a military court persisted in finding Alfred Dreyfus guilty of treason (September 1899), though some of the evidence against him was known to be forged, the government persuaded the president to pardon him in the hope of avoiding further controversy.

The most important measure of the later part of Waldeck-Rousseau's administration was the Associations Act of July 1901, which abolished all restrictions on the right of association for legal purposes. This freedom was withheld from religious associations, however, because they were directed from abroad. Waldeck-Rousseau personally thought the act too severe to the religious congregations. He resigned because of ill health in June 1902 but emerged from retirement to protest against the interpretation of the law by his successor, the militantly anticlerical Émile Combes (Combes, Émile), who refused to authorize any religious associations and was responsible for the closing of thousands of Roman Catholic schools.