It happened about 4:50 p.m. on US 301 near Mobley Road, near Lucama.
A spokesperson for the Highway Patrol said a vehicle was traveling south in the northbound lane of US 301 and crashed head-on into another car heading north on US 301.
The wrong-way vehicle burst into flames after the impact and the other car overturned and went off the right shoulder.
All four occupants -- two in each vehicle -- died at the scene.
Highway 301 in Lucama was closed in both directions. That stretch of roadway reopened about 8:30 p.m.
4 killed in fiery two-car crash on Highway 301 in Wilson County
Those who live nearby told ABC11 that wrong-way drivers are common along that stretch of road.
"I've almost been hit by a wrong-way driver and I'm pretty sure a lot of people have out here. It's scary," said Amy Thompson.
"Even if the car is not on your side, I have second-guessed myself a million times. They look like they are coming at you," said Jasmine Maull.
After the crash, Maull said the first thing she did was look for her own children and make sure they were okay.
"As a mother, my heart hurts. As a family member, my heart hurts for those people," said Maull.
Neighbors gave their condolences to the lives that were taken suddenly in the fiery crash.
"I'm thinking about the families right now. It's a lot to be going through, especially right after the holidays, right before Christmas," said Thompson.
The identities of the victims have not yet been confirmed, the Highway Patrol said.