He was a member of the Liberal Party of Colombia; he served as congressman (1931-1935), Minister of Education, Minister of the Interior and Minister of Foreign Affairs, during the governments of Alfonso López Pumarejo and Eduardo Santos. He served too as acting President of Colombia between 1945 and 1946. He then served as the first secretary general of the Organization of American States from 1948 to 1954. Finally, he served as President of Colombia between 1958 and 1962. During this later term, he founded the Colombian Institute for Agrarian Reform (INCORA), with the intention of implementing a needed degree of land reform in the country.
In 1931 he married Berta Puga, and together they had four children: Alberto, Ximena, Marcela and Consuelo Lleras Puga.