In 1908, his first composition, Purita, was dedicated to the first Carnival Queen, Pura Villanueva, who later married the distinguished scholar Teodoro Kalaw.

In 1934, the President of the university, Jorge Bocobo, launched a committee to collect and document folk songs of the Philippines.

Part of this committee were dancer Francisca Reyes-Aquino, who notated numerous folk dances and compiling them in several books, and composer Antonino Buenaventura, who transcribed numerous folk music, including those accompanying the dances recorded by Reyes-Aquino.

On February 5, 1945, during the Liberation of Manila, while the family was escaping their neighborhood due to constant bombing, a cart full of Santiago's compositions and manuscripts caught fire near the burning Quiapo Church.

Santiago, along with other composers like Nicanor Abelardo and Jose Estella, contributed to the "artsification" of kundiman as a genre.

Surviving compositions of Francisco Santiago mostly consist of published songs, piano works, and a few others in manuscript.

Francisco Santiago's Piano Concerto was considered one of his masterpieces, alongside his Taga-ilog Symphony.

However, in 1952, Santiago's former colleagues and students spearheaded by his pupil and pianist Juan C. Bañez reconstructed the Concerto entirely from memory.