The blast happened around 4:15 a.m. Friday at 3428 Hwy 117 Alternate - formerly the Goldwater Motel.
Deputies say the force of the explosion knocked down the front wall of one of the hotel rooms.
Three people who were in or near the room were taken by helicopter to UNC Hospitals in Chapel Hill.
A fourth was being treated at Wayne Memorial Hospital.
The injured were identified as Tracy Grady, 41, of Dudley; Joshua Franklin Summerlin, 21, of Mount Olive; Regina Rugkit, 28, of Goldsboro; and Randy Johnson, 27, of Mount Olive.
The SBI is assisting the Wayne County Sheriff’s Office with the investigation.