Colegio de San Juan de Letran was formed through the union of two Intramuros institutions dedicated to educating orphans: the Colegio de Niños Huérfanos de San Juan de Letran, founded by Don Juan Geronimo Guerrero, and the Colegio de Huérfanos de San Pedro y San Pablo, established by Dominican brother Diego de Santa Maria. Given their shared goals and strong connections, these institutions merged in 1630 to form the Colegio de San Juan de Letran. 

The Colegio's name honors the Basilica of Saint John Lateran in Rome, and its chapel received similar privileges. Saint John the Baptist for whom the Basilica is named, is also the patron saint of Letran.

In 1690, Letran was declared as an ecclesiastical college. And in 1738, six scholarships were granted by the King of Spain to students from China, Japan, and Vietnam, including St. Vicente Liem de la Paz. A royal decree in 1865 elevated Letran to a First-Class College, and its curriculum was modernized in 1886. Further expansions occurred with the American influence in 1900.

A new building was constructed in 1937, but it was damaged during World War II and temporarily relocated to the Dominican church of San Juan del Monte. The Colegio resumed its operations in Intramuros in 1946.

Throughout its history, Letran has produced notable alumni such as Manuel Quezon and Sergio Osmena. Despite numerous challenges, the institution has consistently upheld its mission to provide high-quality Christian education, remaining true to its principles of DEUS, PATRIA, LETRAN.