The Canada Southern Station, completed in 1873, embodies the contribution the city of St. Thomas made to the railroad industry in North America. During its busiest period, in the 1920s, as many as 2,000 passengers passed by the station per day.

The building was constructed between June 1871 and April 1873. Once completed, the Canada Southern Railway Station worked double-duty. The passenger station occupied the ground floor and the corporate headquarters of the Canada Southern Railway (CSR) were located on the upper floor.

A large formal dining room, which occupied approximately a third of the ground floor, served meals to passengers. Modest living-quarters for the kitchen staff were located on the second floor.

The CSR built 31 railway stations in Ontario during the 1870s; the station in St Thomas stands out from the rest in two respects. It is the largest of them all and the only one that was built in the Italianate style of architecture. The building comprises two storeys and is 107.9 metres (354 feet) long and 10.9 metres (36 feet) wide, and has 162 arched windows. It took 400,000 white bricks to construct the station. The exterior was painted red at a later date.

Originally, the station had eight chimneys and a canopy that wrapped around the entire building; the chimneys were dismantled over time and the canopy was removed in the late 1960s.

Over the years, the station was owned by various railroad companies, including: the Canada Southern, Michigan Central, New York Central, Pennsylvania Central, Conrail, and Canadian National/Canadian Pacific. It is presently owned by the North America Railway Hall of Fame.

The St. Thomas station stands as a reminder of the intense competition amongst regional rail lines in the 19th century and of the influence of foreign capital in railway construction and profitability.