Crews arrived just before 3 p.m. to find one vehicle with heavy front-end damage still on the roadway, and the second vehicle off the road down an embankment.
One person had to be extricated by Branson firefighters using the Jaws of Life. The patient was flown by Mercy Lifeline to a trauma center in Springfield.
Two patients were transported for medical treatment by the Taney County Ambulance District.
The crash closed the highway for about an hour, with traffic routed through the Welk Resort property.
Branson Police are investigating the cause of the accident.