U.S. Route 22 ran through Monroeville as a substantial business route. When the Parkway East (I-376) was extended east to connect to the Pennsylvania Turnpike, U.S. 22 was shifted to that road, and the original U.S. 22 stretch of William Penn Highway became Business U.S. 22. Today, U.S. Route 22 runs through the municipality, serving as its main business district. This highway, along with the Pennsylvania Turnpike (Interstate 76), the eastern portion of the Penn-Lincoln Parkway (Interstate 376 concurrent with U.S. 22), U.S. Route 22 Business, and PA Route 48 intersect in Monroeville. Exit 57 (old Exit 6) of the Pennsylvania Turnpike is in Monroeville, with its interchange to Interstate 376. U.S. Route 22 also has an interchange with PA Route 286, which serves the northeastern part of the municipality.