The station was originally opened in 1842 as London Road station, the terminus of the Manchester and Birmingham Railway. The terminal part of the station contains 12 platforms, while the busiest part of the station is platforms 13 and 14 which served the former Manchester South Junction and Altrincham Railway, (opened in 1849), which provides the only through route for trains running through Manchester from southeast to northwest (e.g. Birmingham - Manchester - Preston - Glasgow).
The station was renamed Manchester Piccadilly when it was rebuilt in 1960 for the new electric train services to London. The glass roof over the terminal platforms was completely replaced in the late 1990s, and the remainder of the station was rebuilt in 2001-2002.
In the mid 1990s the station undercroft (2 levels below the main rail platforms) was converted to provide two platforms for the Manchester Metrolink tram system, where Piccadilly station is currently the terminus for services to Bury, Altrincham, and Eccles.
Piccadilly station handles approximately 1,000 train movements daily.