Refusing to take the teacher's oath of loyalty to the French Second Empire of Napoleon III, Buisson went to Switzerland, teaching philosophy at Neuchâtel from 1866 to 1870. In 1867 he took part in the first Geneva peace conference, where he advocated a United States of Europe. After the fall of Paris in the Franco-German War of 1870–71, he organized an asylum for war orphans.

Under the French Third Republic Buisson was appointed inspector general of the Paris public schools in 1871, but he was forced to resign for recommending the elimination of religious instruction. As national director of elementary education (1879–96), he aided Premier Jules Ferry in drafting statutes that took the public schools out of church control (1881, 1886) and made primary education free and compulsory (1882). After teaching at the Sorbonne (1896–1902), he sat in the national Chamber of Deputies (1902–14, 1919–23).

In 1898 Buisson helped to found the Ligue des Droits de l'Homme (League of Human Rights). His peacemaking efforts as its president from 1913 to 1926, including the period of World War I, in addition to his postwar work for Franco-German amity, earned him the Nobel Prize.