State troopers say the ambulance ran off the right side of I-20 near the U.S. 378 exit in Lexington County around 12:40 p.m. Tuesday, hitting a sign and a tree.
Troopers say the ambulance then went back across the highway, striking the concrete wall in the median.
Authorities say 51-year-old Richard Bryant of Stanley, N.C., died at the hospital, while the driver and a paramedic suffered minor injuries.
The coroner's office says Bryant died from chest injuries suffered in the crash. He was being taken from a burn center in Augusta, Ga., to a hospital in Winston-Salem, N.C.
The Highway Patrol's special investigation team is looking at the wreck.