In 1853, a group of businessmen from Arkansas, Kentucky, and Tennessee met in Benton, Missouri to organize a railroad. Led by Judge Noah Handy of Charleston, they formed the Cairo Fulton Railroad.
When John Sikes founded the town of Sikeston in 1860, he made sure to set aside property on the track thus assuring Sikeston a railroad depot at some time.
Sikeston was a supply depot of such importance in the Civil War that the tracks between Sikeston and Charleston were torn up to stop supplies from arriving in the area. The Cairo Fulton was the only railroad to add track during the Civil War. After the war, the railroad became known as the CAT Line…Cairo through Arkansas to Texas. The Cairo Fulton defaulted on bonds issued by the state of Missouri after the war, and ownership was transferred to the Iron Mountain Railroad.
In 1916, the Iron Mountain began building the present depot. Soon after the building was constructed, the line was acquired by the Missouri Pacific Railroad Company. It remained a Missouri Pacific station until the company merged with Union Pacific in 1982.