I-44 begins in Wichita Falls and runs due north to the Texas-Oklahoma border at the Red River. Texas holds I-44 as the shortest segment of the freeway as there are only 14 miles of that highway within the state.
I-44 in Oklahoma is a toll road most of the way, paralleled by former U.S. 66 from Oklahoma City to the Missouri state line. In southwestern Oklahoma, I-44 is the H.E. Bailey Turnpike and follows a north-south direction. In the Oklahoma City metro section range from 6-8 lanes, also I-44 overlaps I-35 for a short time in Oklahoma City. From Oklahoma City I-44 shifts its direction to east-west and follows the Turner Turnpike until Tulsa. As I-44 leaves Tulsa it becomes the Will Rogers Turnpike to the Missouri border.
I-44 enters Missouri southwest of Joplin at a point near the corner of Oklahoma, Missouri, and Kansas. It misses the state of Kansas by less than 200 yards. A marker is erected at the point, which can be visited on State Line Road after exiting at U.S. Route 166. The road continues through the south edge of Joplin, then continues east on the pathway of US 166 to Mount Vernon. At the northeast part of Mount Vernon, I-44 heads northeast, while old US 166 continued east on Missouri Route 174. The section of road to Halltown is a completely new road, not bypassing any previous highways. At Halltown, the road follows the general pathway of US Route 66 all the way to downtown St. Louis.
I-44 passes through Springfield on the north side of the city and continues northeast. At Waynesville, I-44 enters a very hilly curvy area until it passes Rolla. Although the road still passes through some hilly areas, none are as steep as that particular stretch.
At Pacific, I-44 begins to widen to six lanes, later to eight lanes. The interstate continues into the suburbs of St. Louis, finally ending near the Mississippi River at the intersection with I-55.
At some places, an "Alternate I-44" is posted. One such ran between Rolla and Springfield via U.S. Route 60 and U.S. Route 63 and another ran via US 63 and U.S. Route 50 between Rolla and Union. These were done to provide traffic relief during road work. The latter of these alternate routes detoured traffic around three hour delays due to road work near Cuba.