The intent of the Denison and Southeastern Railway, chartered on July 27, 1877, was to build a railroad line connecting the towns of Denison and Greenville to the south. They completed the first 20 miles of track between Denison and Whitewright in the early 1880s.

In March of 1880, the D&S was acquired (along with the nearby Denison and Pacific Railroad) by the Missouri-Kansas-Texas Railroad, which renamed the line the Missouri, Kansas & Texas Extension Railway Company. In November of the following year, the line was merged entirely into the MKT's system. Consequently, the MKT was considered the first railroad to enter the state of Texas from the north. By this time, the remainder of the line between Whitewright and Greenville, 32 miles, had been completed.

In 1989, the MKT was merged into the Missouri Pacific Railroad (itself a subsidiary of the Union Pacific Railroad). To shed excess trackage as a result of the acquisition of the MKT, UP abandoned the section of the D&S between its northern terminus at Denison and a connection with a Texas Northeastern line (formerly UP, nee Texas & Pacific's Transcontinental Division) at Bells, TX, in 1990. The D&S continues southward from Bells to Greenville and is still in use.

Today, only a few artifacts remain along the abanodned right-of-way of the Denison and Southeastern Railway.