It happened near the Highway 15-501 exit. The accident involving a tractor-trailer and three smaller vehicles blocked the westbound lanes around 3:30 p.m.
Pictures from Chopper 11 HD showed a pickup truck carrying ladders literally wrapped around the front of the truck.
Nearby, an unidentifiable vehicle was completely burned out. Just to the east, the third vehicle had major damage to the front and rear.
The NC Highway Patrol says the damage is extensive.
"This is one of the worst I've seen in a long, long time, especially with the number of vehicles involved," said Sergeant Jeff Gordon, NCHP. "But anytime you have a major interstate such as this -- you have higher speeds and when we do have those collisions, they're pretty dramatic in nature."
Westbound I-40 was immediately closed. Drivers were detoured through Chapel Hill while emergency crews sifted through the wreckage of a tractor trailer, a box truck and three passenger cars. One of the passenger vehicles caught fire.
Traffic was at a standstill for hours with some motorists trying to avoid an earlier wreck on I-85.
"I actually came this way to avoid the other accident," one motorist said. "I came down this way. Got here before the ambulances did and I couldn't go any further."
"We were actually on the highway, and we got routed off," Durham resident Sherry Adams added. "Now, we're headed back that way, hoping we can get through."
Three people were killed in the crash. The names of the victims have not been released.
Authorities say the death toll could rise.