The two-car collision happened on the N7 outbound at Kingswood near the Newlands Cross Flyover, at around 12:20am on Monday.
The driver of one of the cars, aged in his 40s, was pronounced dead at the scene and his body was removed to Dublin City Morgue.
A male in his 30s was taken to Tallaght Hospital with life-threatening injuries, while another male in his late 20s was taken to Tallaght Hospital to be treated for non-life threatening injuries.
Another male in his 40s was treated at the scene but did not require hospital admittance.
The road was closed temporarily for Forensic Collision Investigators to carry out an examination and has now reopened.
As one of the vehicles came to the attention of gardaí prior to the incident, the incident has been referred to the Garda Ombudsman and investigation is ongoing.