The accident happened on I-40 near NC 42 in Johnston County just before 10 p.m. Thursday.
Authorities said 20-year-old Terri Reeves was driving a 2006 Mitsubishi Eclipse east on I-40, with 22-year-old Joshua Witherspoon in the passenger seat, and 22-month-old Shelby Witherspoon in the back seat, when it ran off the road.
The car ran into the grass median, through the cable guardrail, and into the westbound lanes of I-40.
A 2005 BMW X5 hit the Eclipse first, and then it was struck by a 2005 Lexus. The Lexus also hit the Eclipse.
Authorities said they believed Reeves and Witherspoon were killed instantly in the crash. The little girl was trapped in her car seat for almost 30 minutes while crews worked to free her.
The toddler was transported to WakeMed Hospital and was later flown to UNC-Chapel Hill in stable condition.
The driver of the BMW, 61-year-old James Roland Smith Jr. and his wife 53-year-old Sherri Smith, were also taken to WakeMed. Sherri Smith remained hospitalized Friday.
The driver of the Lexus, 60-year-old Holly Latty-Mann, suffered minor injuries but was not taken to the hospital.
Authorities are still investigating the accident.