The Iowa and Saint Louis Railroad was formed in 1901 with the intent to run from Centerville, IA to Saint Louis, MO. Coal was prolific in the Chariton River Valley; in some cases, it was so close to the ground surface in the valley that most farms had their own mines to extract what they needed and sell the rest. The I&StL was built for this purpose: hauling coal from the Chariton River Valley. Other commodities included timber, general freight and also passenger service.

The I&StL reached as far north as Sedan, IA, via trackage rights on the Chicago, Rock Island & Pacific. The southern end was at Mercyville, MO, a half-mile northeast of Elmer, MO, where the Santa Fe had a station.

One of the main facilities of the I&StL was at Novinger, where the railroad crossed tracks with the Quincy, Omaha and Kansas City Railroad. There was a large yard for handling freight cars interchanged with the QO&KC. In addition, several steam locomotives were stationed at Novinger for local runs to both the north and south, as well as switching duties at the yard and the QO&KC interchange. While there was a roundhouse and locomotive shop at Novinger, most of the heavy maintenance was performed at the shops in Milan, MO. The I&StL was subsequently bought by the QO&KC; both railroads were finally merged into the Chicago, Burlington & Quincy.

Abandonment of the line came in sections: the line from Sedan, IA to Novinger, MO was abandoned in 1936, as was the line between Mercyville to South Gifford; from South Gifford, the line was abandoned to the Baiotto mine spur (which served Billy's creek mine, northeast of Youngstown, MO) in 1942. Final abandonment came before 1950 when the Kirksville to Green City line was abandoned.

The right-of-way is still marked on topographical maps.

See also The Quincy, Omaha and Kansas City Railroad.