As early as World War I, Guèye made radical demands for genuine assimilation of Africans into French culture and institutions. In the early 1920s he became the first African lawyer from French West Africa to study in Paris. After serving as mayor of Saint-Louis, Senegal, for a brief time in the mid-1920s, he was sent by the French to the Indian Ocean island of Réunion as a judge and remained there until 1933. In 1934 and 1936 he ran (and was defeated) for deputy to the French National Assembly. Also in 1936 he became political director of the new Senegalese branch of the French Socialist Party.

After World War II Guèye and his protégé Léopold Senghor were elected to the French National Assembly (1945) and reelected the following year. Guèye also became mayor of Dakar, a post he held until 1961. Senghor, however, turned to the rural masses for a broader base of support and left the Socialists in 1948 to form his own party, which rapidly became dominant in Senegalese politics. Guèye, appealing mainly to a limited electorate of urban professional bourgeoisie, lost his National Assembly seat in the 1951 elections and was never again a threat to Senghor’s leadership. Finally in 1958 he joined Senghor’s new party, the Union Progressiste Sénégalaise, and in 1959 was elected president of the Senegalese Legislative (later National) Assembly, where he remained until his death.