The crash has been cleared. Motorists are still advised to exercise caution and drive safely.
According to a NSW Ambulance media spokesperson, one adult and three children have been transported to Bowral and District Hospital.
There is no information on their condition at this stage, the spokesperson said.
One driver said a caravan had been destroyed in the crash.
"The caravan is a complete write-off. Everything was strewn all over the road," they said.
A Mittagong Rural Fire Service crew has left the scene after providing fire protection.
Bowral and Mittagong Fire and Rescue crews was also at the scene for HAZMAT assistance.
Traffic is building in the area, with queues of about 10 kilometres.
Motorists are advised to exercise caution and allow extra travel time.
A traffic management spokesperson has indicated that southbound traffic delays are now eight kilometres long. Motorisits are advised to exercise caution and to allow additional travel time.
A hazmat team are on the scene as they decanter fuel from one of the vehicles. Additionally there is diesel on the road.
A car and caravan crash has closed one southbound lane on the Hume Highway.
The collision, which happened just before 10am, was north of Green Hills Road.
Motorists travelling southbound are experiencing about 3.5 kilometres of delays.
According to a NSW Ambulance media spokesperson, a 50-year-old woman is conscious and breathing.
There are reports of neck pain, back pain and head pain however there is no bleeding, the spokesperson said.
Two children aged eight and 12 were also involved in the crash.
Police and ambulance have been called to the scene. Traffic control and a tow truck is on the scene.