The Ohio & Mississippi was planned to extend west-ward from Cincinnati to a point on the great river directly opposite St. Louis, with a branch from North Vernon, Indiana, to Louisville, Kentucky. Although a railroad between the then two most important cities of the West was dimly projected as early as 1832, the railroad was not chartered until February 14, 1851, in Illinois. Preliminary surveys were commenced on November 1, 1848, but actual construction on the west end was not started until February, 1852. By the terms of the charter granted by the Legislature of Indiana, the company was authorized to locate and survey a railroad on "the most direct and practical route between Lawrenceburg, on the Ohio River, and Vincennes, on the Wabash River."

The organization of the Ohio and Indiana portions of the new line was completed in 1850, and Abner T. Ellis, of Vincennes, was elected president. A number of substantial citizens of Vincennes and Cincinnati and the intermediate towns between were chosen as directors. The contract was let in January, 1851, for the building of the road between the Ohio and the Wabash. Actual construction was started in April, 1852.

The charter of the State of Illinois provided that the building of the western division should be begun before February 12, 1852, and actual construction was started on February 7. The western division was the first to be completed and the City of Vincennes had to wait nearly two years for the eastern division to be completed. But on April 15, 1857, that city witnessed the joining of the rails which completed a railroad all the way from Cincinnati with the Marietta and Cincinnati R.R., which, in turn, connected at Parkersburg, Virginia, with the Baltimore and Ohio R.R., this completed a great rail route that ran all the way from the eastern seaboard to the Mississippi River.

The Ohio and Mississippi was originally built as a six-foot gauge line. This made interchange with standard gauge railroads a bit difficult, as through-cars had to be jacked up and the trucks changed. To overcome this it was decided to change the entire railroad to standard gauge in one day. This was done on Sunday, July 13, 1871. At daylight, three gangs of men began work on each section of about three miles in length, the first gang drawing spikes and throwing nails, the second gang spiking and the third gang setting rails to gauge and lining up the track. The change on the entire 340 miles of track was made in about eight hours. Changing engines and cars had begun about eight months previously and there was no interruption to business.

The O&M was formally taken into the Baltimore and Ohio family on November 1, 1893, and merged with the M&C to form the Baltimore and Ohio Southwestern Railway Co. This company was reorganized in 1899 as the Baltimore and Ohio Southwestern R. R. Co. and it is one of the wholly-owned subsidiaries of the Baltimore and Ohio Railroad