A fourth man, also in his 20s, is being treated in hospital for serious injuries.
The collision took place in the Omagh Road area of Garvaghy.
PSNI Inspector Hicks said: “At around 1.50am, it was reported that a car and a lorry were involved in the incident.
“Three males, all aged in their 20s sadly died at the scene.
“A fourth male, also in his 20s, was taken to hospital for treatment to serious injuries.”
The Omagh Road remains closed in both directions between the Curr Road and the Greenmount Road, as motorists are advised to seek alternative main routes for their journey.
Police have appealed for anyone who was in the area at the time and may have witnessed the incident or who has dashcam footage or any other information, to contact them on 101 quoting reference number 240 27/12/21.