Emergency crews responded to a report of a single motor vehicle collision at 7 p.m. on Eramosa-Garafraxa Townline between County 29 and Third Line.
Police said the driver of the pick-up truck was ejected and investigators are still trying to determine if he was wearing his seatbelt.
The 29-year-old man was rushed to a local hospital with life-threatening injuries, but has since been taken to a trauma centre in Hamilton.
The road was closed for several hours Sunday night, but has since reopened.
OPP are asking witnesses of the crash to call investigators at 1-888-310-1122.