The 46-year-old man was driving his Mercedes Sprinter van south on the A702 at Lamington when the crash happened at around 8.45am on Wednesday.
Police said it appears the vehicle lost control and came off the road.
Emergency services attended, however the 46-year-old man was pronounced dead at the scene.
Police are appealing for information about the incident.
Sergeant Grant Neilson from the Trunk Road Patrol Group based at Motherwell said: “Inquiries are continuing into the cause of the crash and I would appeal to anyone who witnessed the crash who has not yet spoken to police, or anyone driving on that road shortly before the crash took place to contact our office through 101 quoting reference number 0806 of May 30.”
The road was closed while officers carried out their investigations.
A report will be sent to the procurator fiscal.