Construction on the railroad (formed during an 1846 meeting at the Hannibal office of John Marshall Clemens, father of Mark Twain)[1] began in 1851 from both cities.

[2] The line started westward from Hannibal and ran through the Missouri cities of Palmyra, Monroe City, Lakenan, Shelbina, Clarence, Anabel, Macon, Bevier, Callao, New Cambria, Bucklin, Brookfield, Laclede, Meadville, Wheeling, Chillicothe, Utica, Mooresville, Breckenridge, Nettleton, Hamilton, Kidder, Cameron, Osborn, Stewartsville, Hemple, Easton, before arriving in St. Joseph.

The first experiment in distributing mails in so-called "post offices on wheels" was made in 1862 by William A. Davis between Hannibal and St. Joseph, Missouri.

It was intended to expedite the connection at St. Joseph with the overland stage, which had replaced the Pony Express routes to the West a year earlier.

In 1867 a consortium of Charles E. Kearney, Robert T. Van Horn, and Kersey Coates persuaded the railroad to build a cutoff at Cameron to Kansas City, Missouri.

Today, four miles (6 km) of track between Brookfield and Laclede remain, and is primarily used for surplus rail car storage on the (now) BNSF Railway.