The 84-year-old woman, who has not yet been named, was pronounced dead at the scene on the A1, near Morpeth, Northumberland.
The police were called at just after 3.50pm on Saturday after witnesses saw a car driving southbound on the northbound side of the road.
Northumbria Police said that minutes later the car crashed into the central reservation after colliding with cars travelling the other way.
A 51-year-old man from another vehicle was airlifted to the Royal Victoria Infirmary in Newcastle with chest and abdominal injuries and is said to be in a serious condition.
A 52-year-old female passenger from the same car was also taken to the hospital, where her condition is described as serious but not life-threatening.
Several other cars were also hit in the incident but the occupants sustained only minor injuries.
Inquiries are still being carried out by Northumbria Police's Motor Patrols officers, who are keen to speak to any witnesses.