Emergency services were called to the Great Western Highway in Blackheath at about 7pm.
It’s believed a semi-trailer and a Subaru sedan collided head-on before the truck crashed into a Toyota Corolla.
The Subaru and Toyota drivers were trapped and had to be freed by police and firefighters.
The Subaru driver, a 27-year-old man, was treated for serious leg and chest injuries at the scene before being taken to hospital in a stable condition.
His passenger, a two-year-old boy, was treated for head injuries and taken to hospital in a critical condition.
The Toyota driver, a 29-year-old man, was treated for internal injuries and taken to hospital in a stable condition.
The truck driver, a 46-year-old man, was treated for minor injuries and taken to hospital for mandatory testing.
The Great Western Highway was closed for several hours but has re-opened this morning. Drivers are urged to take care on the road.