The truck, which was carrying garbage, then swerved into westbound traffic, crashed and caught fire.
Crews reopened I-40 around 2:30 a.m. Tuesday.
Troopers say the driver of the tractor-trailer is in critical condition in the burn unit of UNC Memorial Hospital.
The driver of the Isuzu, 28-year old Omar Perez-Vincente, is in serious condition at WakeMed.
Troopers say he caused the crash and charges will be filed when he leaves the hospital.