Santa Mesa was opened on December 22, 1905 as a station originally situated on the Antipolo Line of the Manila Railroad Company, the first station building was erected with galvanized iron materials, it was rebuilt in 1920 as a larger concrete structure followed by installation of two sidings on the opposite side.
The current station building was built in the 1962. During the Northrail-Southrail Linkage Project from 2007 to 2009, raised platforms for Hyundai Rotem DMUs were built west of the station building, the platforms are currently being extended to accomodate 5-car EMUs and provide more shelter.
- The current Southbound platform of Santa Mesa station was originally an island platform.
- Santa Mesa is one of the three railroads whose station building was erected with galvanized iron, the other is Marikina (still existing), the San Isidro, Nueva Ecija station on the Cabanatuan Line was later replaced with adobe stone.
- Santa Mesa serves the Polytechnic University of the Philippines.
- When the Santa Mesa underwent several renovations since the introduction of the Metrotren and the Filtrack, the main station building dates back from 1962.