Before the Overland Trail was the Cherokee Trail, which was established in 1849 as a shortcut to the gold fields of California, as it is 150 miles shorter than the Oregon Trail. In 1856, after Lt. Francis T. Bryan announced that he had discovered a “good Indian trail along the south side of the South Platte,” the US Army began using the route. In 1858 the army undertook many improvements, making it more attractive as a stagecoach route and path to the Rocky Mountains for gold seekers, and the Overland Trail in Colorado was established.

In addition to spreading disease, the massive amount of travelers on the trail reduced grazing lands and diminished important sources of game and shelter for American Indians. By 1862 hostilities between whites and Native Americans along the Oregon Trail were increasing to such an extent that much of its traffic, including the US mail, was moved south to the Overland Trail. That same year, Ben Holladay, a famed transportation entrepreneur known as the “Stagecoach King,” saw a potential money-making opportunity and bought a failing stagecoach company. Holladay supplied his newly formed Overland Mail & Express Company with sturdy Concord coaches and numerous new stage stations; a telegraph line was installed along the trail in 1863.
By early 1864, the Civil War required Union troops guarding the Overland Trail to turn their attention elsewhere, leaving travelers susceptible to attacks by Native Americans. In the early fall of 1864, conflict with Native Americans had increased so much that the government closed the Overland Trail, resulting in serious repercussions for the residents of Colorado: mail delivery was slowed to a crawl, and food was in short supply.

The year 1865 was a very violent one along the Overland Trail in Colorado. Nearly all the ranches along the route were burned, and Julesburg was essentially destroyed. Despite the continuing hostilities, in 1866 Wells Fargo bought the Overland Mail & Express Company from Ben Holladay for $1.8 million dollars.

The advancing railroads overwhelmed the stagecoach travel industry within a few years. The Union Pacific Railroad arrived in a rebuilt Julesburg in 1867, and in 1869 the Battle of Summit Springs marked the last of the major Native American hostilities on Colorado's Great Plains. Despite improved safety for travelers along the Overland Trail, the US government entered into a mail delivery contract with the railroad, effectively eliminating the majority of operating capital for the stagecoach companies. In 1870 the last stagecoach on the Overland Trail reached Denver, along with the first train.