Mesquite Flats was first settled by Mormons between 1878 and 1882, when fifteen families consisting of seventy-one individuals began to farm the area. In June 1882, however, the Virgin River flooded and washed out their canals. They began to rebuild, but soon abandoned their efforts. In 1887, Dudley Leavitt and family again attempted to settle at Mesquite Flats, but after their own battles with the elements too chose to leave after four years. A final attempt was made in 1894, when six families rebuilt the canal, this time met with success, and finally the town was established. In 1898, the name was shorted to just "Mesquite", and by 1900 nineteen families had settled there.

Agriculture was always Mesquite's primary staple, and farmers grew cotton, alfalfa, wheat, cane, and figs, and during the 1906 San Francisco Fair even grapes and pomegranates from Mesquite took first place. The town was also a dairy center, with five dairies in operation during the twentieth century. It's location on one of the United States' first automobile highways - the Arrowhead Trail - also provided a boost as motels and campgrounds were opened to serve travelers.

At the end of the twentieth century and into the 2000s, Mesquite saw its largest period of growth. Casinos were opened, providing a nearer source of entertainment than Las Vegas to residents of Utah and Arizona, and the City of Mesquite was formally incorporated in 1984. From 1990 until 2000, the population soared from less than 2000 to over 9000, a number which more than doubled by 2020. Despite its incredible growth, today only a few remnants can be found of Mesquite's earliest days.