Both the ambulance and vehicle were seen from SkyEye flipped over on the side of the road off Zamanek Road at FM 1994.
Deputies said it happened just after 4 a.m. Three people, two paramedics and a patient, were in the ambulance. They were taken to the hospital and suffered minor injuries.
One person in the vehicle was trapped. The fire department had to extricate him. He was taken to the hospital by a helicopter and is stable.
Crews shut down FM 1994 eastbound, and the westbound lane was being diverted to Brumbelow during the investigation.
DPS investigators are trying to figure out what caused the crash.