Interstate 64 is a major east–west corridor that stretches from the Midwestern heartland to the Atlantic coast. The route begins in Wentzville, Missouri, a western suburb of St. Louis, where it connects with I-70. From there, it travels through southern Illinois, Indiana, and Kentucky before entering the Appalachian region. In West Virginia and Virginia, the highway winds through mountainous terrain and historically significant cities, ultimately terminating in Chesapeake, Virginia, near the Atlantic Ocean.

Notably, I-64 links several major urban centers including St. Louis, Louisville, Lexington, Charleston, and Richmond. Its path offers a blend of metropolitan travel and scenic drives—especially in Kentucky’s Bluegrass region and the rugged sections of the Appalachian Mountains. This makes it an important route not just for commerce and commuting, but also for tourism and long-distance travel.

Throughout its length, I-64 overlaps with other major routes, including concurrencies with I-55 and I-57 in Illinois, I-75 in Kentucky, and I-77 in West Virginia. Its role in connecting the Midwest to the Atlantic coast makes it a vital transportation artery in the eastern United States.