The victim has been named by police as 50-year-old Gary Wilson from the Lisburn area.
Mr Wilson was the driver of one of the vehicles involved in the crash at the junction of Old Ballynahinch Road and Comber Road, on the outskirts of Lisburn, which happened shortly before 7am.
Three ambulance crews were dispatched and a doctor also attended the scene.
Firefighters used specialist cutting equipment to free Mr Wilson, who was trapped in one of the vehicles.
Tragically, he was confirmed dead at the scene.
Lagan Valley MLA Edwin Poots, who lives close to the scene of yesterday’s crash, said it happened at a “notorious accident blackspot”.
He added: “Sadly, this is not the first death to have happened at this junction. It is a particularly fast section of road and the sight lines are not the best.
“Some improvements have been made by Roads Service in the past, but more needs to be done.
“My thoughts and prayers are with this man’s family.”
DUP Councillor Uel Mackin said: “We don’t know exactly what caused this crash as yet, but this is a very dangerous junction.
“There have been a series of accidents and sadly some fatalities at this blind crossroads over recent years and myself and my colleagues have been lobbying for safety improvements to be carried out.”
Tributes have been paid to Mr Wilson by his son, Gary, and on social media.
Mr Wilson’s death was the third to happen on Northern Ireland’s roads since Friday.
A 66-year-old man died following a two-vehicle crash in Newry on Sunday afternoon.
The fatal collision, involving a motorcycle and a Land Rover Discovery SUV towing a caravan, happened on the Warrenpoint Road shortly before 12.30pm.
On Friday, three-year-old Christopher Ward died after being struck by a vehicle in Bessbrook, Co Armagh.