A Volkswagen Golf and Vauxhall Corsa were involved in the collision on Liverpool Road, Haydock, at about 19:20 GMT on Sunday, Merseyside Police said.
A 16-year-old boy and 12-year-old girl, who were passengers, in the auto are both in hospital in a serious condition. Their condition is described as serious.
Police said the 27-year-old male driver of the Corsa was being treated for minor injuries in hospital.
A third male in the auto (who is not related) aged 29 was also injured and his condition is described as critical.
Anyone who witnessed or has any information on this incident can call Matrix Roads Policing Officers on 0151 777 5747. Alternatively call the 101 number quoting incident reference number 887 of 17 December, or Crimestoppers anonymously on 0800 555 111.