The crash happened in the afternoon about 180 miles northeast of Phoenix, according to the Arizona Department of Public Safety (DPS).
Two adults and two teens were killed in the van, reports ABC Las Vegas affiliate, KTNV.
Officials said the van was making an illegal left turn onto U.S. 93 when it collided with the bus. There were no Cowboys players on board.
The crash had shut down at least one lane of the highways that served as the main route between Las Vegas and Phoenix, according to KTNV.
Four Cowboys staff members -- including a writer, a team mascot, a videographer and the bus driver -- suffered only minor injuries, according to ABC Dallas affiliate, WFAA.
The team was supposed to do a meet-and-greet in Las Vegas on their way to preseason training camp in California, according to the Dallas Cowboy's website.