In Missouri, the stretch was originally labeled as the Daniel Boone Expressway then only as US 40, and, as such, is still known to some locals in Greater St. Louis as Highway 40, even though the road has been designated as both I-64 and US 40 since 1988.

In April 2007, construction started to rebuild 10.5 miles (16.9 km) of I-64 in St. Louis from Spoede Road to Kingshighway.

On December 6, 2009,[2] with a grand opening ceremony and dedication, I-64 was completed in its entire length in Missouri from the Poplar Street Bridge to I-70 in Wentzville.

The portion of I-64 in St. Louis has been named the Jack Buck Memorial Highway, in honor of the late sportscaster.

I-64 enters Illinois from St. Louis, Missouri, via the Poplar Street Bridge, where it overlaps I-55 as it crosses the Mississippi River.

After crossing the city of East St. Louis and the rest of suburban St. Clair County, the freeway heads southeast through rural Southern Illinois.

After providing access to towns such as Carlyle, Breese, Nashville, and Centralia, the freeway overlaps I-57 through the Mount Vernon area for approximately five miles (8.0 km).

In addition, there are several points, especially in the very sharp valleys along its route in Dubois, Perry, Crawford, and Harrison counties, where the highway towers more than 100 feet (30 m) above the surrounding terrain.

Moving eastward, I-64 passes through Shelbyville, Frankfort, Midway, Lexington, Winchester, Mount Sterling, Owingsville, and Morehead, before leaving the state near Ashland at Catlettsburg.

It overlaps I-75 as it makes an arc around the northeast of Lexington's urban core, with the exit numbers for I-75 used for the concurrent portion.

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.

I-264 intersects the beltway, providing access to other parts of Norfolk and Chesapeake and extending east to the Oceanfront.

Access to the Oceanfront area is accomplished from I-64 via a portion of I-264, a roadway originally built as the Virginia Beach Expressway, funded by tolls to retire revenue bonds.

It is also worth noting that the apparent route of I-64 would have taken it through the southern end of Carlyle Lake which was also under construction at this time.

[14] On September 9, 2011, the Sherman Minton Bridge was closed down by Indiana Governor Mitch Daniels after construction crews found cracks in the main load bearing structural element.