The original cathedral in what was the city of Puerto Rico (changed to San Juan Bautista in 1521) was constructed from wood in 1521. It was destroyed by a hurricane and the current structure constructed in 1540, being reshaped in later centuries, the last time being in 1917.

The first school in Puerto Rico was the Escuela de gramática (Grammar School). The school was established by Bishop Alonso Manso in 1513, in the area where the cathedral would later be constructed. The school was free of charge and the courses taught were Latin language, literature, history, science, art, philosophy and theology.

The cathedral contains the tomb of the Spanish explorer and settlement founder Juan Ponce de León. It also has a shrine to the Blessed Carlos Manuel Rodríguez Santiago, the first Puerto Rican, the first Caribbean-born layperson in history to be beatified.

The first organist of the Cathedral of San Juan was the Canarian Domingo Crisanto Delgado Gómez who came from the island of Tenerife and managed to take this position in 1836, having been a composer in Cathedral Our Lady of Los Remedios of San Cristóbal de La Laguna in his native island