In Missouri, the stretch was originally labeled as the Daniel Boone Expressway then only as US-40, and as such, is still known to locals in the St. Louis area as Highway 40, even though the road has been designated as both I-64 and US-40 since 1988. An interchange at Highway N O'Fallon, Missouri opened on December 13th 2004. This interchange will also accommodate the future tie in of the Route 364 freeway to I-64.
I-64 enters Illinois from St. Louis, Missouri, via the Poplar Street Bridge, where it overlaps I-55 and I-70 as it crosses the Mississippi River. After crossing the city of East St. Louis and the rest of suburban St. Clair County, the freeway quickly enters rural Southern Illinois. Shortly after passing Mid-America Airport at Exit 23, I-64 enters Clinton County, then Washington County. After providing access to towns such as Carlyle, Nashville, and Centralia, the freeway overlaps I-57 through the Mt. Vernon area for approximately five miles. East of Mt. Vernon in Illinois, services along I-64 are few. The freeway crosses Jefferson, Wayne, and White counties as it progresses east toward Indiana and the Evansville area. East of the St Louis area, there are numerous oil wells dotting the landscape.
I-64 crosses the Wabash River and enters the state of Indiana. It passes Indiana 69 and Indiana 165, and also passes under Indiana 68 (no direct interchange serves Indiana 68, though one can access said route from either Indiana 165 or 65) then passes three officially marked exits for Evansville (Indiana 65, US 41, and Interstate 164/Indiana 57/Future Interstate 69) then proceeds through part of the scenic Hoosier National Forest, with service exits leading to Jasper, Santa Claus and Indiana 37, and intersects Interstate 265 in New Albany before crossing into Kentucky on the Sherman Minton Bridge.
Interstate 64 enters into Kentucky at Louisville, paralleling the Ohio River along the Riverfront Expressway. It junctions with several downtown interchanges before coming to the Kennedy Interchange, where it intersects Interstate 65 and Interstate 71 in a tangle of ramps often referred to as the "Spaghetti Junction." Moving eastward, I-64 passes through Shelbyville, Frankfort, Lexington, Winchester, and Morehead, before leaving the state near Ashland at Catlettsburg. It overlaps Interstate 75 as it makes an arc around the northeast of Lexington, with the exit numbers for I-75 used for the concurrent portion.
Interstate 64 travels for 184 miles within the state of West Virginia, passing by the major towns and cities of Huntington, Charleston, Beckley, and Lewisburg. It has only two major junctions within the state: Interstate 77 in Charleston and in Beckley. It also crosses the Kanawha River a total of 4 times in a 20 mile stretch (twice west of Charleston, immediately before entering the downtown Charleston area, then approximately 5 miles east of downtown Charleston).
Between I-64's two junctions with I-77, I-64 and I-77 overlap. From the final crossing of the Kanawha River east of Charleston to their split at Exit 40 south of Beckley, the two Interstates are tolled, forming a part of the West Virginia Turnpike.
While the two expressways overlap, the exit signs are those for Interstate 77. Thus, eastbound travellers entering from Kentucky will see exit numbers increase until Exit 60, at which time Interstate 77's exit numbers are used, decreasing from Exit 100.
Interstate 64 in Virginia runs east-west through central Virginia from West Virginia via Covington, Lexington, Staunton, and Charlottesville to Richmond. From Lexington to Staunton, it overlaps Interstate 81 (using I-81 exit numbers). From Richmond, Interstate 64 continues southeasterly through Newport News and Hampton to the Hampton Roads Bridge-Tunnel, and then through Norfolk and a small portion of Virginia Beach to end in Chesapeake.
At its eastern terminus, East I-64 is actually running westbound (and West I-64 eastbound), as the route forms a fishhook around Norfolk.