The Rimrock Springs bus rolled and landed on its side across the median on Interstate 90 early Sunday, investigators said.
Several passengers were thrown from the bus and two of them died at the scene, the patrol said.
Many passengers were pinned beneath the bus when authorities arrived.
"In 16 years I haven't seen anything like this," Montana Highway Patrol Sgt. Scott Hoffman told The Missoulian. "So many people laying on the ground with injuries, writhing in pain. It was a terrible scene."
The bus company did not release the name of the driver, who was among the survivors He was previously a driver for Greyhound.
"He is a solid driver, with no issues of reliability," said Dan Ronan, senior director of communications for the American Bus Association.