I-44 is one of five Interstates built to bypass US 66; this highway covers the section between Oklahoma City and St. Louis.

Virtually the entire length of I-44 east of Springfield, Missouri, was once US 66, which was upgraded from two to four lanes from 1949 to 1955.

In the US state of Texas, I-44 has a short, but regionally important, 14.77-mile (23.77 km) stretch, connecting Wichita Falls with Oklahoma.

The route runs almost due north to the Texas–Oklahoma state line at the Red River.

I-44 provides access to downtown Wichita Falls and Sheppard Air Force Base.

The Interstate passes through the suburbs of St. Louis and then into downtown St. Louis, passing the Gateway Arch before finally terminating near the Mississippi River, continuing from there as I-70 from the west end of the Stan Musial Veterans Memorial Bridge.

I-44 traffic wishing to continue northeast and east must use the Poplar Street Bridge and I-55/I-64 to cross the Mississippi River.

The latter of these alternate routes detoured traffic around three-hour delays due to road work near Cuba.

I-44 was originally signed in 1958 as an Interstate designation of the Turner Turnpike linking Oklahoma City and Tulsa and the Will Rogers Turnpike linking Tulsa and the Missouri state line southwest of Joplin, along with the US 66 bypass in Tulsa that linked that city with the two turnpikes and the continued four-lane highway from the Missouri border to an interchange with US 71 south of Joplin previously designated as US 166.

I-44 was extended in 1982 southwest of Oklahoma City along the existing H. E. Bailey Turnpike, thus raising the milemarkers by about 100.

The addition of the new section was unusual in that it is a more north–south segment and did not directly connect to the previous western end at I-35.

As of April 2006[update], the rocks carved away for the new roadbed have virtually no lichen, reflecting that this construction occurred rather recently.