The blue Mazda Premacy was travelling south on the M74 when it veered off the road close to Junction 13, near to Abington Services, at around 2am on Wednesday.
Emergency services went to the scene and the 29-year-old driver was taken to Wishaw General Hospital where he later died.
The 25-year-old passenger in the vehicle sustained minor injuries.
Police are appealing for information about the one-vehicle crash.
Sergeant John Tait of the Road Police Unit, said: “We are appealing for anyone who was travelling on the M74 near to Abington in the early hours of this morning who may have seen this vehicle, or anyone who may have dashcam footage, to get in touch.
“Anyone with information should contact Police via 101 quoting incident number 0185 of Wednesday December 5 2018.”