The line connected the second and third largest cities in the state of Missouri prior to the American Civil War. The stage route that it paralleled previously been called the "Hound Dog Trail".
The line started westward from Hannibal and ran through the Missouri cities of Palmyra, Monroe City, Shelbina, Clarence, Anabel, Macon, Bevier, Callao, New Cambria, Bucklin, Brookfield, Laclede, Meadville, Wheeling, Chillicothe, Mooresville, Breckenridge, Nettleton, Hamilton, Kidder, Cameron, Osborn, Stewartsville, Hemple, Easton, before arriving in St. Joseph.
John Rogers, well before he became a popular 19th century American sculptor, worked in 1856 and 1857 as a mechanic on the railroad. Abraham Lincoln rode the route in 1859 en route to a speech in Council Bluffs, Iowa.
The first assignment of Col. Ulysses S. Grant during the American Civil War was protecting the railroad and Pony Express mail. Grant was promoted to brigadier general in August 1861 after the assignment. Shortly after Grant left his assignment, the railroad experienced its worst disaster of the war on September 3, 1861, when bushwhackers burned a bridge over the Platte River, causing a derailment that killed between 17 and 20 and injured 100 in the Platte Bridge Railroad Tragedy.
From its experiences with the Pony Express, in 1864 the railroad also created the first railway post office for sorting mail on the train en route in the United States (although too late for the Pony Express use).
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. The railroad, through its subsidiary Kansas City and Cameron Railroad, built a shortcut and the 1,371-foot ( m) Hannibal Bridge over the Missouri River in downtown Kansas City. The bridge established a direct overland link between Chicago and Texas. It was the first rail bridge across the Missouri River when it opened July 3, 1869, and established Kansas City rather than Leavenworth or St. Joseph as the dominant city in the region.
The Chicago, Burlington and Quincy Railroad had used the railroad for through traffic to Chicago almost from the start and in 1883 it formally acquired it. The connection by rail between Hannibal and St. Joseph remained in place for about 125 years. On March 2, 1970, the railroad became the property of Burlington Northern after the CBQ merged with 3 other railroads to form the new railroad company. However during the mid-1980s, the railroad discontinued service from Brookfield westward to St. Joseph. Today, a four mile stretch of track between Brookfield and Laclede remain in place and is primarily used for surplus railroad cars along what is now the BNSF Railway which instead of running west to St. Joseph now runs southwest toward Kansas City. The tracks from Laclede westward to St. Joseph are no longer in place, while the tracks from Brookfield eastward toward the Mississippi River are still in use today by the BNSF.