It was planned to span the distance between the seaport of Mobile, Alabama and the Ohio River near Cairo, Illinois.

The first section of track opened for service in 1852 between Mobile and Citronelle, Alabama and was constructed in 5 ft (1,524 mm) gauge.

[4] The line made it to Columbus, Kentucky on April 22, 1861, steamboats were then used to connect with the Illinois Central Railroad at Cairo.

Following the conflict the M&O had to be almost entirely rebuilt and was facing near total financial ruin due in part to an unpaid debt of $5,228,562 that had been owed by the Confederate government.

[2] By 1870 the operators had seen the need to complete the line all the way to Cairo and make it the northern terminus instead of Columbus, but financial problems stood in the way.