The river is named for Thomas Virgin, a member of the first American party to see it, led by Jedediah Smith in 1826. Smith named it "Adams River", after then-president John Quincy Adams, but later explorer and mapmaker John C. Fremont gave it its current name. After the Smith party successfully descended the river on the way to California, Thomas Virgin was badly wounded in an attack by Mohave people during the crossing of the Mojave Desert. Virgin recovered from his wounds but was later killed, along with most of Smith's companions, in an attack by Umpqua people (in present-day Oregon).

The Old Spanish Trail followed the Virgin River for part of its length from near St. George to the point it ascended the Mormon Plateau to cross to the Muddy River in present-day Nevada.