On January 31, 1860, the final spike was driven in Winona, Mississippi, establishing the first ever rail link between the Great Lakes and the Gulf of Mexico.

Confederate soldiers built earthwork fortifications to defend the railroad's Tallahatchie River bridge near Abbeville but retreated south without firing a shot when they learned of a flanking maneuver by Grant.

Illinois Central established their regional headquarters in Water Valley, MS, and based a large maintenance facility there.

Famed engineer Casey Jones regularly operated passenger trains along the line and it was said locals could set their watches by him due to his strict adherence to published schedules.

In 1927, Illinois Central started to shift traffic to their Grenada-Memphis route and closed the maintenance facility in Water Valley.

Finally, in 1982, 30 miles of track between Oxford and Bruce Junction in Coffeeville was abandoned and the remaining northern portion of the line sold.

In February 2016 Roseburg Forest Products, the only user of the railroad south of Holly Springs, announced that it would idle its plant in Oxford, with the last scheduled rail service on March 4.