The crash happened around 8 a.m. near the community of Meadview on the southeastern side of the Lake Mead National Recreation Area, said Mohave County sheriff's spokeswoman Trish Carter.
The bus was headed from Las Vegas to the western rim of the Grand Canyon. The 12 people on board included the driver, who suffered minor injuries and has been cooperating with investigators.
Carter said several passengers suffered serious injuries and were flown to hospitals in Las Vegas and nearby Kingman. The passengers' names were not immediately released, but Carter said they may be tourists from another country.
Authorities did not have details about the owner of the bus.
Sunday's crash marked the third time in two years that the region, home to tourist attractions that include the Grand Canyon and Hoover Dam, has experienced a deadly tour bus crash.
In January 2009, seven people died and 10 were injured when a charter bus carrying a group of Chinese tourists on a return trip from the Grand Canyon crashed on U.S. 93, the main highway leading to Hoover Dam.
In August, three Japanese tourists were killed and 11 others injured when the bus they were traveling in rolled on Interstate 15 in southwestern Utah. They were on a four-day tour of national parks, including the Grand Canyon.