The fur trade in North America reached its height between the 1820s and the 1850s, and it was during this period that business partners Louis Vasquez and Andrew Sublette opened the fur-trading post Fort Vasquez in 1835. They constructed their business venture on the shore of the South Platte River, a location they hoped would be ideal as it was located about halfway between the already-successful Fort Laramie and Bent's Fort.

The trading post itself consisted of a large adobe structure about 100 feet on each side, with walls two feet thick. Mexican workers were hired to construct it, and at its height as many as two dozen traders and workers lived permanently at Fort Vasquez. 

Fort Vasquez was in operation for seven years, until Vasquez and Sublette sold it in 1842. Later that year it was abandoned by the traders who had purchased it. Vasquez and Sublette moved on to work at other trading posts, forts, and outposts around the West. The old Fort Vasquez was briefly operated as a way station for wagon trains, and later the surviving buildings would serve as a bivouac, school, and post office before being incorporated into a ranch. In the 1930s the site was deeded to the county, and the nearby town of Platteville led an effort to rebuild the fort as a museum. The modern reconstruction is smaller than the original and has a different layout, but sits on the original site.

Today, Fort Vasquez Welcome Center is operated by the City of Platteville, while the historic site is maintained and preserved by History Colorado.