Police and ambulance crews were on the scene, near Larkhall, shortly after 9.20am this morning.
It is not yet known whether there are any injuries to drivers or passengers in the two vehicles.
The M74 southbound between junction 12, Millbank, and junction 13.
Police are directing traffic and said there is debris from the crash strewn across the road.
A Police Scotland spokeswoman said: “We were called at 9.20am to reports of a crash between a lorry and a mini bus.
“We have no note of injuries at this stage but officers are directing traffic due to debris across the carriageway.”
Roads have been closed for more than 30 minutes with no reports of when they will reopen.
A spokeswoman for the Scottish Fire and Rescue Service said its crews had not been called to the scene.