The crash, between a blue Peugeot 208 and a green Ford Fiesta, happened at around 3.30pm.
The driver of the Peugeot was pronounced dead at the scene, while the occupants of the Fiesta, a 29-year-old woman and two children aged five and 12 are now in hospital in a serious but stable condition.
A statement from the force said: "The driver of the Peugeot, a 43 year-old woman, was sadly pronounced dead at the scene. Her family have been informed and are being supported by officers.
"The occupants of the second vehicle, a 29 year-old woman and two children aged five and 12, are currently in hospital in a serious but stable condition."
Councillor Kevin Osborne, Labour councillor for the area on Barnsley Council said: “My sincere condolences go out to the deceased’s family and friends and I wish a speedy recovery of all others who suffered injuries in the incident.
“Thanks must go to our emergency services who responded so quickly, including South Yorkshire Police, Yorkshire Ambulance Service, South Yorkshire Fire & Rescue and the Yorkshire Air Ambulance.
“This is a major trunk road into Barnsley and accidents of any kind are of concern. I hope the investigation into the cause of this most recent incident in concluded quickly and any recommendations for future action implemented just as quickly”
The force is now appealing for anyone with information to contact them, particularly those who may have dashcam footage.
Anyone who can help police is asked to call them on 101, quoting incident number 493 of April 4. Any footage can be emailed to [email protected] with the incident number in the subject line.