After school he worked as a journalist and finally in 1913 the owner and publisher founded in 1911 liberal daily El Tiempo, which he built into the largest daily newspaper in the country.
In 1917 he became a member of the Partido Liberal Colombiano and appointed in August 1930 by President Enrique Olaya Herrera as foreign minister in his cabinet, where he remained until July 1931. In 1931 he was for a short time governor of Santander Department in northeastern before he was Head of the Delegation of Colombia at the League of Nations, 1931-1933. In 1935 he was elected Senator and was the Senate ( Senado ) until 1937.
Santos, the leader of the right wing within the party was in 1938 elected unopposed as president.
During his August 7, 1938 to August 7, 1942 permanent presidency, he sat largely continued the reforms of his predecessor Alfonso López Pumarejo. Despite the Second World War started, he led a significant programs that also created the basis for subsequent governments, such as in the areas of housing, credit reforms and highway construction. Another important highlight of his tenure was the conclusion of a border treaty with Venezuela after several years of negotiations. In addition, it also came to a new agreement with the Holy See, which meant that the clerical control of education ended and concluded that the bishops must be nationals of Colombia. Even before taking office, he made it clear that the states of America would have to stick together and therefore broke after the attack on Pearl Harbor in December 1941 off diplomatic relations with the Axis powers. At the same time it came to the nationalization of the previously located in the German -owned national airline Avianca.
After the end of his presidency, he was a leader of the Liberal Party and was 1948-1950 during the tenure of Mariano Ospina Pérez first vice president of the country.
Between 1953 and 1957 he was in his capacity as editor of El Tiempo one of the main critics of dictator Gustavo Rojas Pinilla, who had then close the publishing house for 22 months. However, the offer of a re Erscheines the newspaper under certain conditions, at a press censorship, he refused and began with the publication of El Tiempo again until after the deposition Rojas Pinillas in May 1957. Santos remained until his death the editor of El Tiempo.
To him, the stadium of the football club Unión Magdalena at Estadio Eduardo Santos, as well as a barrio of Medellín was named in honor.
After his death his nephew Enrique Santos became the sole editor of El Tiempo. His son, Eduardo Santos ' great-nephew Juan Manuel Santos is since August 7, 2010 also President of Colombia.