From the beginning it was designed as a central station unifying the lines of the three companies then serving Lyon, which merged to form the Chemins de fer de Paris à Lyon et à la Méditerranée (PLM) as the station was opening.

The station lost its view of the city when an intermodal terminal (combining local public transit and intercity buses) and dual-carriageway highway were built in front of it in the 1970s.

Although much modern building has somewhat tarnished the look of the area, the station retains many of its original features: It is the terminus of Lyon services to and from Paris on the high-speed LGV Sud-Est railway line.

Instead, Lyon-Part-Dieu station, constructed in the 1970s in a large planned business district outside the central city, acts as the more popular embarkation point for most high-speed trains, especially to Paris and the north.

On 5 April 2022,[2][3] Trenitalia France introduced a shortworking service of the Milan–Paris Frecciarossa between Lyon-Perrache and Paris Gare de Lyon, with an intermediate stop in Lyon-Part-Dieu.