The incident happened close to the Old Dublin Road, just south of Newry, at about 15:00 BST on Thursday.
The motorcyclist was taken to a hospital in Belfast by a police helicopter and is in a serious condition.
The A1 Dublin to Belfast road was closed but has now reopened.
Northbound traffic became backed up as far as Dundalk after the crash.
The southbound lane was closed briefly to allow the police helicopter to land and take off again.
Police are appealing for anyone who witnessed the crash or who may have stopped with the motorcyclist to contact them.
A man in his 40s has been airlifted to hospital after a serious collision involving a motorcycle and a car in County Down.