It happened at Cole Mill Road near mile marker 173 between US 15/501 and NC 147 in Durham.
Investigators said a 2000 Ford Ranger driven by Timothy Glover Jr., 57, of Durham collided almost head-on with a northbound tractor-trailer driven by Robert Christopher Taylor, 37, of Walnut Cove.
After the first collision, the pickup went airborne and hit the driver's side cab of a northbound cement truck driven by Christopher Devon Foster, 37, of Butner.
Two people were hurt. Police said their injuries did not appear to be life-threatening.
A large amount of diesel fuel spilled from the tractor-trailer.
Investigators said they believe Glover got on I-85 going the wrong way at the East Club Boulevard entrance ramp and drove for approximately six miles before the crash.
911 operators took several calls about the truck, and police were looking for it when the accident happened.
Charges are pending. Police said there was no indication Glover was under the influence of drugs or alcohol.
All northbound lanes were shut down at Cole Mill Road as crews worked to clear the scene. Authorities reopened the roadway about 4 hours later.