A woman and a 7-year-old boy are dead after a horror head-on crash south of Sydney.

A woman and a seven-year-old boy have died while his twin sister and another woman are fighting for their lives after a horror head-on crash on the Hume Highway in NSW.

The two-car collision occurred at Pheasants Nest, southwest of Sydney, before 8am on Tuesday, closing the highway’s southbound lanes for more than four hours.

A 49-year-old woman driving a Mazda 4WD died at the scene, police say, while her two passengers, a brother and sister both aged seven, had to be freed from the vehicle by emergency workers.

The driver of a Holden car, also a 49-year-old woman, was trapped for some time as well, before she and the boy were taken to Liverpool Hospital in a critical condition.

However, the boy died several hours later.

The seven-year-old girl, who AAP understands is the boy’s twin sister, remains in a critical condition in the Children’s Hospital at Westmead.

A witness told News Corp Australia he and other drivers stopped to help get the kids out of the car, which was upside down.

“A truckie pulled off the dashboard because the mum was trapped, to try and pull her out,” he said.

“The boy told us it was his twin sister.”

Crash investigators combed through the carnage then reopened the highway just after 12.30pm.

Footage posted on social media shows a smashed-up black vehicle overturned down an embankment and emergency service workers surrounding a silver car on the highway, which had its roof ripped off.

A caller to Sydney’s 2GB radio described seeing a car’s tyre marks leading from the northbound lanes of the highway through the centre nature strip and on to the southbound lane.

“Both cars were absolutely totalled,” the witness said.