Bolded cities are officially-designated control cities for signs
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 . 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 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.
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.
At the time the I-44 designation was assigned in Oklahoma in the 1950s, Oklahoma signed the milemarkers west to east starting at Turner Turnpike's Oklahoma City terminus at the I-44/I-35 interchange (near Edmond). 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 new section was also a violation of the Interstate numbering grid, as it extended south of I-40. (The "44" number indicated that it should lie north of I-40 for its entire length.)
What was once I-244 around St. Louis is currently part of that city's I-270/I-255 beltway.
During the historic 1999 Oklahoma tornado outbreak, an F5 tornado hit Interstate 44. This particular tornado had the fastest tornado wind speeds on record. The interstate was severely damaged where the tornado crossed it. In the end, this tornado was blamed for 36 deaths.
A section of I-44 was moved slightly north between Powellville, Missouri and Doolittle. The old road is highly visible for eastbound traffic near Powellville. As of April 2006, the rocks carved away for the new roadbed have virtually no lichen, reflecting that this construction occurred rather recently.
All business loops of Interstate 44 are located in Missouri. They serve Joplin, Sarcoxie, Mount Vernon, Springfield, Lebanon, Waynesville-St. Robert, Rolla, and Pacific. A business spur links I-44 with Fort Leonard Wood.