Prefontaine tragically died after a car accident in 1975 at the age of 24. His car was flipped with him lying under the wreck. By the time medics arrived, he was pronounced dead. It had been reported that his blood alcohol content was found by the Eugene Police Department to be 0.16. The official cause of his death was traumatic asphyxiation.

On May 30, 1975, on the return from a party and dropping off of a friend, Frank Shorter, Prefontaine was driving down a familiar road, Skyline Boulevard, near Hendricks Park, when his car, a gold 1973 MGB, swerved left and hit a rock wall along the side of the street. The overturned car trapped Prefontaine underneath it.

Pre was killed in a one-car accident in the early hours of May 30 on a wooded hillside street in Eugene, a road he ran over countless times training while attending the University of Oregon. He apparently lost control of his small sports car rounding a sharp curve, crossed the center-line, struck a rock wall and flipped over several times.

According to the Register-Guard, he left the party in his orange MGB convertible at about 12:15 am. After dropping off Alleman and Shorter, Prefontaine headed toward Skyline Boulevard, where his car struck a boulder alongside the road, flipped, and came to rest on top of him. He died before the car could be moved.