By the late 1890s, the Missouri-Kansas-Texas Railroad already had a large volume of freight and passenger traffic along its Clinton-to-Hannibal route which, thanks to a connection with the Chicago, Burlington and Quincy Railroad at Hannibal, was able to reach Chicago. However, Saint Louis, to the east, was developing into an economic and commercial center; considerably closer than Chicago, the MKT was intent on reaching Saint Louis from their existing Clinton-Hannibal line. The MKT created a new railroad entity, the Missouri, Kansas and Eastern Railroad, to accomplish this task.

Construction started at New Franklin, MO, just north of Booneville on the Clinton-Hannibal line, and stretched eastward to Machens, on the Mississippi River, by 1895. As with the route to Chicago, the MKT would gain access to Saint Louis from their terminus at Machens via a connection with the CB&Q. At the junction of both the Chicago and Saint Louis routes, New Franklin became home for the locomotive shops of the MKT.

The Saint Louis line saw considerable swings in traffic volume; the decline of the railroad and the poor condition of track construction did not help matters. Both a trackage-rights agreement on the adjacent Missouri Pacific line to Saint Louis and numerous flooding and washouts spelled the end of the MKT's Saint Louis line, and it was railbanked in 1988.

The Columbia Branch, a short branch line from this line that served the town of Columbia, was abandoned in 1978.

The entire line was donated to the State of Missouri, which now operates the Katy Trail along its length.