Four people were airlifted to Newcastle's John Hunter Hospital following the collision, which resulted in significant delays.

The Pacific Highway was closed in both directions for more than three hours and holidaymakers diverted along The Bucketts Way and Booral Road.

The accident occurred when a southbound Ford utility towing a small caravan, driven by a 63-year-old Cardiff woman and a northbound Ford Courier utility, driven by a 27-year-old Merrylands man, sideswiped on an undivided section of dual carriageway, five kilometres south of Nerong.

Following the impact the two vehicles came to rest on the western side of the highway with the caravan detached from the tow vehicle.

A second northbound vehicle, driven by a 35-year-old Queensland man, struck the detached caravan.

The Westpac Rescue Helicopter Service attended the crash scene and airlifted two males; aged 27 and 12, and two females aged 37 and 59 to John Hunter Hospital with multiple injuries.

One of the four airlifted later underwent surgery.

Two others injured in the accident were conveyed to Bulahdelah Hospital for treatment of minor injuries.

A single lane of the highway was opened to alternating traffic flow following the arrival of the Newcastle Crash Investigation Unit, with the road re-opened to normal traffic flow just before 3.30pm.