A 48-year-old Laurieton man lost his life after sustaining serious injuries as a result of a head-on accident north of Telegraph Point at 6.20pm on Sunday. His life is the fourth lost on the existing highway between the Port Macquarie and Kempsey bypass this year.

Police and emergency services were called to a road works zone on the highway after the two cars collided head-on trapping both drivers in their vehicles.

Emergency services including Fire & Rescue NSW and Rural Fire Service crews helped release both drivers from the wrecked vehicles.

The Westpac Rescue Helicopter flew to the scene with a doctor who performed emergency surgery on-site before transporting one driver to John Hunter Hospital.

The Laurieton man was conveyed to Port Macquarie Base Hospital but later died of his injuries.

A 62-year-old man from Clybucca remains in a serious but stable condition.

The Pacific Highway was blocked for over five hours marking a horror 24 hours on the Port Macquarie to Kempsey stretch which is under heavy construction.

For emergency services personnel, it was a day that tested their resources on a section of the Pacific Highway that is becoming all to familiar and for all the wrong reasons.

Earlier on Sunday, a 33-year-old woman was flown to John Hunter Hospital by Westpac Rescue Helicopter with serious injuries after a car accident near Kundabung. The Pacific Highway was closed northbound after the woman's car left the road north of Smith Creek Road at about 5.50am.

The woman sustained serious injuries to her upper leg, thighs and body after the guard rail on the side of the road went through the vehicle on impact.

A 10-year-old child suffered lacerations and was later transported to John Hunter Hospital while a five-year-old sustained minor injuries.

Sergeant Paul Dilley of Mid North Coast LAC Highway Patrol said Sunday's effort by local emergency services had taken its toll. He implored all motorists to remain aware and vigilant when travelling through this section of highway road works.

"It's a work zone so there is a lot more happening on either side of the road," Sgt Dilley said.

"There are changes to the signposted speed limit at different work sites, there are really not many places to stop on the side of the road anymore for the protection of workers on the highway and there are embankment areas blocked off to stop vehicles going down there.

"What was once considered a relatively decent drive has become more difficult because of the changes to the environment and drivers need to be aware and drive to those conditions."

Member for Port Macquarie Leslie Williams echoed the words of police and urged drivers to be cautious while works continue.

"The NSW government is working harder than ever to complete the upgrade of the Pacific Highway.

"There is a huge amount of work currently underway, not only between Port Macquarie and Kundabung, but right up to the Queensland border," Mrs Williams said.

"I implore motorists to drive carefully, obey the speed limits and slow down in construction zone areas. Since the Pacific Highway upgrade began the number of lives lost has halved - and we expect this number to continue to decline as work progresses along the highway."

The NSW road toll for 2016 now stands at 157 - 35 more than this time last year.

The Roads and Maritime Service said serious road incidents highlight why upgrading the Pacific Highway is critical to improving safety for motorists.

"Since work started on duplicating the Pacific Highway, 437 of the 657 kilometres has been upgraded to four lanes," an RMS spokesperson said.

"Roads and Maritime will continue to monitor the highway and has recently undertaken further line marking and installed road reflectors to improve road safety on the existing highway. Further safety works will be considered until the Pacific Highway upgrade is completed.

"It's important motorists drive to the conditions of the road and make sure they are well rested before heading out."