Arizona Department of Public Service spokesman Bart Graves said the bus is owned by Silver State Transportation and most of the passengers are believed to be from Australia.
The bus was northbound on Highway 93 on Friday night, nearing the Nevada state line, when the driver suffered a physical problem and lost control, Arizona highway patrol spokesman Carrick R. Cook said.
The company that offered the tour said the driver may have suffered a heart attack.
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The vehicle hit a ravine, tore up a small hill, and then bounced and lurched over rough terrain for more than 210m before stopping, damaging the front end but remaining upright, Cook said.
"We believe the driver experienced some sort of the medical condition and he just went off the road," the patrol said in a statement. No other vehicles were involved.
All 48 passengers were injured, but 27 of them were walking wounded with mainly bumps and bruises, Cook said.
"The passengers were pretty much bouncing around," he said.
The six most seriously hurt were flown by helicopter to University Medical Center in Las Vegas, while 15 others with less severe injuries were rushed to area hospitals by road.
UMC spokeswoman Danita Cohen said the six were being treated for nonlife-threatening injuries, such as broken bones and lacerations. She described them as being mostly over 50 years old.
The passengers were returning to Las Vegas following a trip to the Grand Canyon when the crash occurred.
Tony Fiorini, president of Silver State Trailways, the California-based company bus company that operates tours from Las Vegas to the Grand Canyon, said the company believes its driver had a heart attack while on the road.
"Fortunately, no one else was seriously injured," Fiorini said.
Fiorini declined to release the name or age of the driver and didn't say how long the driver had been with the company.
It was the third time in recent years that a tour bus crash in the area claimed lives.
Two years ago, two people were killed and several others injured in a crash on an area highway. 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 US 93, the main highway leading to Hoover Dam.
