Previously, the freeway was a divided highway signed only as US 40 with at-grade intersections, which were slowly converted to limited-access exits.

The freeway travels through the congested Chesterfield Valley, where it gains a fourth lane and then meets I-270 at a flyover interchange built in the early 1990s in the city of Town and Country.

Continuing east, I-64 remains four lanes and travels through the affluent areas of Frontenac and Ladue.

This stretch, located between Ballas Road and I-170, was closed in 2008 for a complete reconstruction, at which point substandard exits were upgraded and the fourth lane was added.

Kingshighway marks the end of the completely reconstructed eastern half, where again outdated exits were updated and shoulders widened.

The Missouri Department of Transportation (MoDOT) rebuilt the stretch of I-64 from Spoede Road to Kingshighway Boulevard between 2008 and 2009.

[2] In 2020, exits 39 and 38B were closed and demolished to make way for the CityPark, a new soccer-specific stadium for St. Louis City SC on the site.