The man was cut free from his vehicle by fire fighters while the horse was killed in the incident.
It is understood the horse escaped from a nearby field.
It was not being ridden at the time but the owner was at the scene shortly after the crash happened on the A71 in Overtown, near Wishaw.
The injured man was trapped in his vehicle as a result of the collision at around 9.50pm on Tuesday night.
Firefighters used special cutting equipment to release the man from his vehicle following the incident.
A spokesman for the Scottish Fire and Rescue Service said: “We received a call from Police Scotland reporting a person was trapped in a car after collision with a horse.
“Operations Control in Johnstone immediately mobilised appliances from both Motherwell and Larkhall community fire stations as well as a supervisory officer.
“Our firefighters deployed hydraulic cutting equipment to successfully free the man from his vehicle, working closely with Scottish Ambulance Service colleagues who were providing medical care at the scene.
“He was then taken by ambulance to Wishaw General Hospital, where everyone involved in this road rescue will wish him well.”
Police officers closed the road to ensure the safety of the public and the casualty.