It happened at about 08:00 GMT on Friday morning on the Belfast Road between Fivemiletown, County Tyrone, and Brookborough, County Fermanagh. The road has since reopened.
The man, who has been named as Daniel Morris, was from the Brookborough area.
Police have appealed for witnesses.
DUP MLA for Fermanagh and South Tyrone, Maurice Morrow, said the crash had "thrown the community into shock".
"There is no good time to suffer such tragedy, but for such an incident to occur at Christmas is particularly severe," he said.
"I am very familiar with the stretch of road in question and have travelled it many times. My thoughts and prayers are with the family and friends of the victim at this extremely harrowing time."
A 37-year-old man from County Fermanagh has died following a one-vehicle road crash.