It is one of the busiest Amtrak stations serving a metropolitan area smaller than two million people, primarily because of the large number of passengers traveling to and from Philadelphia and points east.

It sees twenty-six arrivals by the Keystone Service on weekdays, thirteen from both Harrisburg and New York Penn Station, and seven from each on weekends.

[14] With construction of the Erie Canal and the National Road, the citizens of Philadelphia became worried of the loss of trade to New York City and Baltimore, Maryland, and persuaded the state government to invest in a transportation network to travel west over the Allegheny Mountains.

[17] The legislature revised its plan to include the failed attempt with a connection from the canal terminus in Columbia to Philadelphia.

[19] The Philadelphia and Columbia Railroad opened in 1834, originally with a horse-drawn passenger cars before steam locomotives replaced them as motive power.

[22] On April 28, 1929, the Pennsylvania Railroad completed a cutoff bypassing downtown Lancaster, closing the old station and opening the new depot.

The former Pennsylvania Railroad train was continued by Amtrak Broadway Limited, while the Duquesne was renamed the Keystone.

From 1971 to 1979, Amtrak's National Limited provided service from the station to New York and Kansas City, Missouri.

[31][32] Plans included a new HVAC system, improved ticketing and waiting area for intercity buses, an expanded parking lot, landscaping, a taxi stand, and "a complete rehabilitation of the station's interior and exterior".

[38] By October 2013, most of the interior restoration work, including refurbishment of windows, re-plastering and repainting of walls, and the installation of a new HVAC system, was completed.