Police said six other people also suffered injuries after six cars and two lorries collided at around 4.25pm on Monday.
Emergency services are at the scene of the pile-up at the M74 northbound, between Hamilton and Raith Interchange in South Lanarkshire.
A Police Scotland spokeswoman said the road would remain closed while emergency teams continue to work at the scene. A total of five ambulances are in attendance.
Motorists are facing major delays because of the closure. A diversion through Hamilton has been put in place.