San Pablo was opened on July 3, 1911 alongside the new section of South Main Line between Malvar, Batangas and San Pablo, Laguna as the line's terminus.

Further landmarks from the station include the San Pablo Heritage zone, the city public transport terminal, and Sampaloc Lake.

Farther away are jeeps circling the city and serving nearby towns like Calauan and Alaminos.

The station is also close to Maharlika Highway, a major thoroughfare for buses when traveling to Quezon.

The station is proposed to be a major stop in the South Lang Haul project, connecting San Pablo with Metro Manila and Bicol.