U.S. Route 11 (US 11) runs southwest to northeast across northcentral Alabama for 250.671 miles (403.416 km). It enters the state from Mississippi concurrent with US 80 and exits into Georgia east of Sulphur Springs. US 11 runs through the major cities of Tuscaloosa and Birmingham, as well as the smaller cities and towns of Cuba, York, Livingston, Epes, Boligee, Eutaw, Cottondale, Coaling, Woodstock, Bessemer, Brighton, Midfield, Trussville, Argo, Springville, Ashville, Steele, Attalla, Reece City, and Collinsville. State Route 7 (SR 7) is designated along the entire route but unsigned.

Interstate 65 (I-65) meanders across 366 miles (589 km) of the Alabama countryside linking six of the state's 10 largest cities. The highway links together many important roadways that make commerce inside and outside of the state's boundaries possible. It starts at I-10 near Mobile. The route passes through the major cities of Montgomery, Birmingham, Decatur, Huntsville, and Athens before entering Tennessee in the north near the town of Ardmore, Alabama.