Cooke County assumed its present boundaries in 1857. It was crossed by several early trails, including the Mormon Trail, a branch of the Chisholm Trail, and the Butterfield Overland Mail route. Settlements in the northern extension of the Peters colony reached the southeastern edge of the county by the late 1840s. Fort Fitzhugh was established in 1847 to protect area settlements against Indian raids, the last of which occurred in the western part of the county in January 1868.

Col. William F. Fitzhugh, commander at the fort, proposed that the town be named for his former commander, Gen. Edmund Pendleton Gaines. Gainesville, founded in 1850, has been the county seat since the organization of the county. The southern and eastern parts of the county were settled by people primarily from Tennessee, Arkansas, and Missouri. The western part had only scattered settlements prior to the late nineteenth century, when German land speculators founded the towns of Muenster in 1889 and Lindsay in 1891.

The Denison and Pacific Railway reached Gainesville on November 7, 1879, from the east; it later became the Missouri, Kansas and Texas (Katy) Railroad. The Gulf, Colorado and Santa Fe connected Gainesville and Denton on January 2, 1887, on its way to meet the Atchison, Topeka and Santa Fe at Purcell, Indian Territory. These links provided for the first time a north-south rail line from Chicago to Galveston. The Katy was later extended west toward Wichita Falls.