Police have made a witness appeal following the crash, which closed part of the A64 between Malton and York at around 11.30am yesterday.
One of the women was rushed to Leeds General Infirmary by air ambulance. Another woman was taken to hospital in York, along with a man who had minor injuries.
North Yorkshire Police said the crash involved a black Nissan Qashqai, a black Kia Sorento, a silver Mercedes A180 and a silver Vauxhall Corsa, all travelling Westbound towards York.
The road was closed for around four hours after the crash between Barton-le-Willows and the Jinnah restaurant.
A police spokesperson said: "The two women remain in hospital in a stable condition.
"Officers are appealing for witnesses to the collision or anyone who recalls seeing the vehicles prior to the collision to get in touch as soon as possible to assist the investigation."
Witnesses should call North Yorkshire Police on 101, select option 2, and ask for Leanne Anderson. They can also e-mail [email protected]
People should use the reference number NYP-31052018-0225 when passing on information.