Traffic was banked up for 17 kilometres on the M7 at Prestons following a crash between a truck and two vans during Wednesday morning's peak.
The 47-year-old truck driver was trapped in his vehicle following the crash, which occurred on the south-bound lanes of the M7, near the M5 interchange, just before 7am.
Police said the circumstances of how the three vehicles collided were not yet clear.
The Transport Management Centre said two of three south-bound lanes on the M7 were closed as emergency services arrived and freed the trapped driver.
The CareFlight rescue helicopter landed on the motorway and dropped off a critical care medical team to treat the injured driver.
The man was taken to Westmead Hospital in a stable condition, a CareFlight spokesman said.
Just after 8.30am, south-bound traffic on the M7 was banked up for 17 kilometres, as crash investigators examined the scene and emergency services tried to clear the wreckage. Just after 9.30am, the traffic queue was down to 12 kilometres.
Motorists were asked to avoid south-bound travel on the M7 if possible, or expect significant delays.
It was one of at least three serious multi-vehicle crashes around Sydney during the morning's peak.
Emergency services were called to Warringah Road at Frenchs Forest just after 7.30am after a garbage truck and a Patient Transport Service vehicle collided.
Four people were injured, including two who were initially trapped in one of the vehicles, a NSW Ambulance spokesman said.
The injured were taken to Royal North Shore Hospital for treatment. One had an injured pelvis, and another had neck pain.
An ambulance carrying a patient has collided with a garbage truck at Frenchs Forest. It's believed passengers are trapped @7NewsSydney??? Freya Cole (@freya_cole) April 25, 2017
Police and paramedics were also called to the Princes Highway at Waterfall, near Waterfall train station, after multiple vehicles were involved in a crash in the highway's north-bound lanes about 8.15am.
Two cars ended up in the scrub on the side of the highway.
A NSW Ambulance spokesman said paramedics assessed four patients, one of whom was taken to Sutherland Hospital for further treatment.
Waterfall: Several vehicles involved in crash northbound on the Princes Highway. #Waterfall #7News pic.twitter.com/ifvyCOCQeR??? 7 News Sydney (@7NewsSydney) April 25, 2017
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