This section of the transcontinental interstate begins at the Kansas state line on the Lewis and Clark Viaduct, running concurrently with U.S. Route 24 (US 24), US 40 and US 169, and the east end is on the Stan Musial Veterans Memorial Bridge in St. Louis.

While passing through Kansas City, I-70 is known as the George Brett Super Highway, named after George Brett, the Kansas City Royals’ all-time hits, home runs and runs batted in (RBI) leader, former third baseman and first baseman, and National Baseball Hall of Fame inductee.

East of Blue Springs, I-70 takes on a rural highway as it leaves Jackson County.

The highway remains this way for the next 100 miles (160 km), going through gently rolling terrain while it meets US 65 at a cloverleaf interchange and finally crossing the Missouri River at Rocheport just west of where it reaches the midsized college town of Columbia in the center of the state.

[11] Through Columbia, the highway is lined with restaurants and hotels and can get congested during University of Missouri sporting events.

The highway leaves Columbia after an exit with St. Charles Road on the east end of town.

East of Wentzville, I-70 passes through the bedroom community of Lake St. Louis, then the growing towns of O'Fallon and St. Peters, and finally the historic city of St. Charles.

After interchanges with Route 180 (St. Charles Rock Road) and US 67 (Lindbergh Boulevard), it passes on the southern edge of St. Louis Lambert International Airport and through several bedroom communities—including Edmundson, Berkeley, Ferguson, and Jennings—and crossing I-170 in the process.

They extend approximately eight miles (13 km) from near Union Boulevard to just north of Downtown St. Louis.

The request generated enormous controversy and ultimately 2.5 acres (1.0 ha) was turned over to use for the bridge.

The bridge was named in honor of St. Louis Cardinals baseball legend Stan Musial.

[citation needed] I-70 across central Missouri is one of the oldest stretches of Interstate Highway in the system, as some sections date as far back as the late 1950s.

[citation needed] In May 2023, about $2.8 billion was allocated to widen the interstate throughout the entire state to at least three lanes in each direction.

[20] A March 2010 study[21] of I-70 from the Kansas state line to the I-470 interchange identified several possible improvements, including expanding the freeway from four to eight lanes, adding high-occupancy vehicle or toll lanes, reconstructing the Truman Road interchange, and improving the curves at Jackson Avenue and Truman Road.