Two cars collided on the B6042 Crags Road in Creswell at about 4.45pm. A Peugeot 106 was being driven towards the A60 and a Citroen C2 was travelling towards Creswell.
Two girls, aged five and 22 months, who were travelling in the Peugeot, sustained fatal injuries.
Their 29-year-old mother, who was driving, and their 7-year-old sister were both taken to hospital with minor injuries. The family come from the Worksop area.
The Citroen driver, a 23-year-old woman from Worksop, sustained an arm injury.
The road was closed for several hours.
Police are appealing for any witnesses to the collision to ring the witness appeal line on 01773 572929 and leave a message.