The 34-year-old, originally from Belfast, passed away at Letterkenny General Hospital.
He has been named locally as Ciaran Parker who was understood to be living in Letterkenny.
He is the sixth person to die on Donegal’s roads in just over a week.
The man suffered severe injuries when his car was in a collision with a lorry between Raphoe and Rossgier at Tullyrap just after 1pm on Thursday afternoon.
Two people in the car were rushed to Letterkenny University Hospital but the man passed away overnight in the Intensive Care Unit.
Another young woman injured in the car is described as being in a stable condition in Letterkenny University Hospital.
A full investigation into the cause of the crash has been launched.
The latest death comes as gardaí appeal for people across Donegal to slow down, wear seat belts, and not to drink and drive.
Head of the Donegal Traffic Corps, Inspector Michael Harrison, appealed to people to respect the roads.
“It has been shown that speeding, not wearing seat belts, and drinking and driving are the three main contributory factors in road deaths.
“We are pleading with people to respect all these factors when getting into their cars. Please respect the roads.
“Donegal has now suffered the loss of six young people on our roads in the space of a week.
“We do not need any more deaths,” he said.
He also appealed to anyone who may have witnessed any of the three accidents to come forward.
Separately, a woman in her 60s died yesterday in a collision between a car and a bus on the main road between Belfast and Dublin, near Hillsborough in Co Down.
Elsewhere, a 50-year-old man died when the motorbike he was riding hit a roundabout in Comber Road at Newtownards at around 11.40pm on Thursday night.