The Lehigh Valley has three major highways: Interstate 78, a major east-west highway, runs through the southern part of the Valley, duplexed with Pennsylvania Route 309. I-78 runs from Harrisburg in the west to the Holland Tunnel and New York City in the east.

U.S. Route 22 is a major freeway that runs through the Valley from Kuhnsville in the western part of the Valley to Easton in the eastern part of the Valley. U.S. Route 22 starts in Cambridge, Ohio in the west, running through the Valley to Elizabeth, New Jersey in the east. A third highway, Pennsylvania Route 33, runs north-south through the Lehigh Valley, from the Poconos in the north to Northampton County in the south.

Other major roads in the Valley include MacArthur Road (PA 145), a divided local road that leads to the Lehigh Valley Mall and its surrounding commercial district. Cedar Crest Boulevard, a north-south highway, runs from South Whitehall Township in the north through west-side Allentown to Emmaus in the south. Lehigh Street runs from Bethlehem in the east, through Allentown, to Emmaus in the west. Tilghman Street runs from Fogelsville in the west to MacArthur Road (PA 145) in the east. Tilghman Street runs through most of Allentown and also intersects with Cedar Crest Boulevard, Pennsylvania Route 100, Pennsylvania Route 309 and several other major Lehigh Valley highways.