Two cars collided on the N15 near Rathcormack at 11.50 am on Sunday.
One of the drivers, a man in his 40s, was pronounced dead at the scene, while a passenger of the same car was treated at the scene.
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A woman in her 30s, who was driving the second car, was airlifted to University Hospital Galway. She remains in a serious condition.
Both passengers of the second car were also brought to hospital with serious injuries.
The road is closed and anyone with information or dash-cam footage is asked to contact Sligo Garda station (071 915 7000), the Garda Confidential Line (1800 666 111) or any Garda station.
