The two-car collision happened on the A34 at The Fillybrooks, near Stone, at around 4.50pm on Sunday.
Emergency services were sent to the scene and four people from the cars involved - a Ford Grand C-max and a Mercedes AMG A-class - were taken to hospital.
A 73-year-old man and a 74-year-old woman, who were travelling in the grey Ford, then died in hospital in the early hours of Monday morning. A 17-year-old girl who was travelling with them was unhurt.
A man aged 29 and woman aged 24, who were travelling in the Mercedes, were seriously injured but are now said to be in a stable condition in hospital.
A spokesman for Staffordshire Police said the family of the victims had been informed and were being supported by specially-trained officers.
"Formal identification will take place in due course and a file will shortly be prepared for HM Coroner," they added.
Police, paramedics and Staffordshire Fire and Rescue Service crews from Stafford and Stone were all sent to the scene.
Anyone who witnessed the collision, or who may have CCTV or dashcam footage of the area at the time of the incident, is asked to contact Staffordshire Police on Facebook, Twitter, or call 101, quoting incident number 451 of January 16.
Alternatively, the Collision Investigation Unit can be contacted directly at email@example.com