The Ohio and Mississippi Railroad was chartered in Indiana in 1848, in Ohio in 1849, and in Illinois in 1851. It was constructed by two companies, the section from Cincinnati to the Indiana and Illinois State line being known as the Eastern Division, and that in Illinois as the Western Division, the gauge, as originally built, being six feet, but reduced in 1871 to standard. The banking firm of Page & Bacon, of St. Louis and San Francisco, were the principal financial backers of the enterprise. The line was completed and opened for traffic, May 1, 1857.

The following year the road became financially embarrassed; the Eastern Division was placed in the hands of a receiver in 1860, while the Western Division was sold under foreclosure, in 1862, and reorganized as the Ohio & Mississippi Railway under act of the Illinois Legislature passed in February, 1861. The Eastern Division was sold in January, 1867; and, in November of the same year, the two divisions were consolidated under the title of the Ohio & Mississippi Railway.

The Springfield Division was the result of the consolidation, in December, 1869, of the Pana, Springfield & Northwestern and the Illinois & Southeastern Railroad - each having been chartered in 1867. The new corporation took the name of the Springfield & Illinois Southeastern Railroad, under which name the road was built and opened in March, 1871.

In 1873, it was placed in the hands of receivers; in 1874 was sold under foreclosure, and, on March 1, 1875, passed into the hands of the Ohio & Mississippi Railway Company. In November, 1876, the road was again placed in the hands of a receiver, but was restored to the Company in 1884. In November, 1893, the Ohio & Mississippi was consolidated with the Baltimore & Ohio Southwestern Railroad, which was the successor of the Cincinnati, Washington & Baltimore Railroad, the reorganized Company taking the name of the Baltimore & Ohio Southwestern Railway Company.