It happened along Interstate 85 near exit 179 for Club Boulevard.
Authorities said around 12:15 a.m., a red Hyundai Sonata and a Ford Expedition with a Pennsylvania license plate collided in the northbound lanes of I-85.
Police said the woman driving the Hyundai was headed the wrong way. The woman, identfied as Aretha Lynette Chavis, 49, of Durham, was killed.
"She was my best friend, my sister, my rock, my everything," Chavis' friend Janet Roberts said.
Roberts owns the Hyundai Sonata. Chavis was driving alone when the car collided with the Ford Expedition.
The driver of the SUV - 29-year-old Jerry Alamo of Central Falls, Rhode Island - was also killed. A passenger - 36-year-old Glenda Alamo - suffered critical injuries.
The other passengers - three children (ages 4, 10 and 11) and four adults (ages 16, 21, 22 and 32) - were taken to the hospital for treatment.
WATCH: Raw video from the crash scene
Durham police told ABC11 that Alamo and Chavis were killed instantly
Police are trying to learn why Chavis got on the interstate in the wrong direction.
"They called me first. I was the only number that they knew," said Chavis' cousin Robbin Chavis Williams. "My cousins called me and said 'she's gone' and I said, 'no she's not.' But now she's gone and there's no better person in the world."
Northbound lanes of I-85 reopened just before 5:30 a.m. after being closed for several hours.
The crash remains under investigation.