The collision happened around 4.10pm on Wednesday on the M74, near to junction 14 at Crawford.
It involved a black Porsche Cayman travelling south, and a white Ford Focus and red Vauxhall Corsa, both heading north.
The 42-year-old man driving the Porsche died at the scene. No-one else was in his car.
The 34-year-old woman driving the Corsa was taken to the Queen Elizabeth University Hospital in Glasgow for treatment to serious injuries.
Her passenger, a 32-year-old man, was also seriously injured and is being treated at hospital in Wishaw.
Both are said to be in stable conditions.
The 55-year-old woman driving the Focus was also taken to hospital in Wishaw where she was treated for minor injuries before being discharged.
The motorway was closed fully until around 11pm for a collision investigation.
Police Inspector William Broatch, of Police Scotland’s Road Policing Unit, said: “Tragically as a result of this collision one man has lost his life and our thoughts are with his family and friends, along with those of the other injured parties.
“We would ask anyone who saw this crash, or the vehicles immediately prior to the collision, to come forward and speak with officers.
“Anyone travelling on the motorway recording with dash cam should check their devices and provide any relevant footage to us as soon as possible.
“There were many vehicles affected by the road closure last night and officers worked to alleviate the traffic build-up as quickly and safely as possible.
“I would like to thank motorists for their co-operation and understanding as we responded to this incident.”
Anyone with information on the incident is asked to call Police Scotland on 101 quoting incident number 0364 of August 12.