It was likely to be part of the route traveled by Meriwether Lewis from Harper's Ferry to Pittsburgh in 1803. and was the route along which telegraph lines first entered Pittsburgh. There are relatively few roads connecting the floodplain of the Monongahela River with the higher elevations to the south and west of the river. Originally, Brownsville road connected with the floodplain by the road now known as Arlington Avenue. In 1851 a turnpike company was chartered by the State of Pennsylvania to pave the Pittsburgh end of the road, and to connect it with South Eighteenth Street. Aften this construction, the northern end of Brownsville Road connected to S. Eighteenth Street, just south of the Pittsburgh, Virginia and Charleston Railway. Many cemeteries were sited along the road as part of the Rural Cemetery Movement. In the 1880s, an "electric road" was built from Mount Oliver to the Concord Presbyterian Church, an area of Carrick also known as Crailo or Spiketown. Brownsville Road became a route out of the city for amusement and entertainment, including prize fighting.
Streetcar tracks of the Pittsburgh Railways Co. ran down the road until 1971, ending just past the border of Pittsburgh at the "Brentwood Loop". They were part of the 53 Carrick, the 53's rush-hour variant 47 Carrick via Tunnel, and the 77/54 North Side–Carrick via Bloomfield ("Flying Fraction"), streetcar runs.