The station is situated in the east end of Old Toronto, south west of the intersection of Main Street and Danforth Avenue.

Because of a lack of available land to expand their existing downtown yard, the Grand Trunk Railway (GTR) decided to build a new freight yard on farmland south of Danforth Avenue where the line to Montreal crossed Dawes Road, which had to be closed and traffic diverted to a new street called Main.

The GTR became part of Canadian National Railway in 1923, and by the 1940s the north yard was no longer used for freight and the roundhouse was demolished.

Wooden stairs and walkway between the Main Street bridge and the railway signal masts connected the ticket booth to the eastbound platform.

[10] Main-Danforth has been identified by Metrolinx as a transportation mobility hub as it is located at the interchange of two or more current or planned regional rapid transit lines.