In the mid-1850s, Mormons established a Mormon Fort at Las Vegas. By the mid-1850s, the route now known as the Salt Lake Road in California, and the California Road in Utah Territory, was a wagon trade route between the two.

In 1849, this road became known as the 'Southern Route', the winter route of the California Trail from Salt Lake City to Los Angeles during the California Gold Rush. In 1847, Jefferson Hunt and other Mormon Battalion members returning to Salt Lake City from Los Angeles pioneered a wagon route through the County that became the Mormon Road. What is now Clark County was acquired by the United States during the Mexican–American War, becoming part of the northwestern corner of New Mexico Territory. Frémont added Frémont's Cutoff on his return from California to Utah in 1844.

In Clark County it was northward away from the Colorado to a series of creeks, waterholes and springs like those at Las Vegas, to which John C. Called the Armijo Route of the Old Spanish Trail, the route was later modified into the Main Route by the passing merchants, trappers, drovers, Ute raiders and settlers over the years by moving to a more direct route. Word of their journeys inspired the New Mexican merchant Antonio Armijo in 1829 to establish the first route for mule trains and herds of livestock from Nuevo Mexico to Alta California through the area, along the Virgin and Colorado Rivers. Previously part of the Mexican Territory of Alta California, the Clark County lands were subsequently traversed by American beaver trappers. Paiutes moved into the area as early as AD 700. Native Americans lived in the Las Vegas Valley beginning over 10,000 years ago. The Las Vegas Valley, a 600 sq mi (1,600 km 2) basin, includes Las Vegas and other major cities and communities such as North Las Vegas, Henderson, and the unincorporated community of Paradise. The county was formed by the Nevada Legislature by splitting off a portion of Lincoln County on February 5, 1909, and was organized on July 1, 1909. Las Vegas, the state's most populous city, has been the county seat since its establishment.

It covers 7% of the state's land area but holds 73% of the state's population, making Nevada the most centralized state in the United States. It is by far the most populous county in Nevada, and the 11th most populous county in the United States. Most of the county population resides in the Las Vegas Census County Divisions, which hold 2,196,623 people as of the 2020 Census, across 435 square miles (1,130 km 2). As of the 2020 census, the population was 2,265,461. Clark County is a county located in the U.S.

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