In the middle of the 19th century, rail service transporting freight was established in Greensburg. Soon after, passenger service began and heavy traffic created the need for a depot. The Pennsylvania Railroad constructed a small white frame structure near the current Station to serve passengers and the ever-increasing freight. The original depot was uThe economic boom created by coal and Greensburg's growing importance as a retail and industrial center convinced the Pennsylvania Railroad to build a better station. The railroad then commissioned architect William Cookman to design the new station for Greensburg. At that time, it was also necessary to redesign the tracks to accommodate the increased rail traffic and the spurs that had been added. The new design elevated the tracks to lessen the west-bound grade and removed a tunnel under Main Street and Maple Avenue. By removing the tunnel, a gap was created in the hill and bridges were built over the span. During this time, the arch over College Avenue was also constructed.

The Station and rail tracks through Greensburg were heavily used both for freight and passengers until the late 1940s. As America began to depend more on automobiles and the highway system, passenger travel slowed. In the late 1960s the Pennsylvania Railroad merged with the New York Central Railroad to create the Penn Central Railroad. The Penn Central later sold off many properties including the station at Greensburg and for a time passenger travel was suspended.

Amtrak restored passenger service to the Main Line in 1977, the same year The Station was placed on the National Register for Historic Places. The Greensburg Station is now one of the most heavily used stops on the Amtrak route to Pittsburgh, Philadelphia and/or New York City. Today the Station is the property of the Westmoreland Cultural Trust which houses offices, a restaurant/brewery and other retail spaces.