The present station, which opened to passengers on October 26, 1959, was built by the Southern Pacific Railroad to replace the former Grand Central Station which was located just to the east of the current property. That station operated from September 1, 1934 until the property was sold to the U.S. Government in 1959 to become the site of the Houston main post office. Grand Central Station, in its turn, replaced the original Houston & Texas Central depot of 1886. When Amtrak was created it was one of two train stations in Houston that served Amtrak trains, the other being Union Station, which is now part of Minute Maid Park. All Amtrak trains were moved to Southern Pacific Station by the end of July 1974, and all trains were either canceled or rerouted out of Houston except the Sunset Limited. This station continued to be owned and operated by the Southern Pacific Railroad after the creation of Amtrak, and has been owned and operated by the Union Pacific Railroad since the merger of Southern Pacific and Union Pacific.
A third station, the Katy Railroad Depot, was located at the top of the Main Street viaduct, adjacent to the campus of the University of Houston–Downtown (UHD). It had ceased to be an active passenger station by the end of 1958 and never served Amtrak. It was demolished, save for a section of platform under the Main Street viaduct.
Whenever the funding becomes available, the current Amtrak station was to be replaced by the Houston Intermodal Transit Center, located just north of downtown, on the Union Pacific Main line. It was planned to be a much larger facility, with the tracks running underground, similar to the design of Penn Station in New York. The project was cancelled in 2010.