On June 24, 1784, King Carlos III of Spain gave the deeds to about 2 km2 (0.77 sq mi) of land that was part of the Hacienda de Mayhaligue to the San Lazaro Hospital which served as a caring home for lepers in Manila at that time.

At the Santa Cruz Parish, a small park was built that linked the area into the headquarters of the Spanish cavalry, the building that once was the Colegio de San Ildefonso, operated by the Jesuits.

During World War II, the Japanese occupational forces, caught unaware of the fast approaching liberation by the combined American & Filipino soldiers from the north, abandoned in 1945 the northern banks of the Pasig River including Santa Cruz.

Today, the church architecture employs a California Spanish Mission style facade silhouette with the usual Filipino (Asian-Hispanic mix) Baroque ornamentation.

As of February 2024, the Manila Department of Education lists three senior high schools in Santa Cruz, namely Cayetano Arellano, Manuel L. Quezon (SHS) and Doña Teodora Alonzo.