At the age of 17 he became teacher of his primary school and there developed his lifelong reformist and anticlerical orientation. He supported General Venustiano Carranza's campaign against the government of Victoriano Huerta, and when Carranza was elected president Calles was appointed minister of commerce, labor, and industry. In 1920 he was a leader in the revolt that overthrew Carranza. He served as secretary of the interior under President Alvaro Obregon from 1920 to 1924. Elected president in 1924, Calles continued Obregon's progressive and democratic policies, which led to a civil war fomented by the Roman Catholic Church over separation of Church and State, especially as applied to the schools. His term expired in 1928, but his influence over the Mexican people and his dominance of national politics continued over the next six years. His chosen successor, President Lazaro Cardenas, radicalized the Mexican Revolution even further and obliged Calles to move to the United States in 1936.
Married Natalia Chacón (deceased). And latterly, Leonor Llórente (deceased). Children: Plutarco, Hortensia, Natalia, Ernestina, and Alicia.