The Princes Highway is blocked in both directions after a cement truck rolled at Tempe.
Paramedics are treating at least one person who is trapped at the scene.
An Ambulance Service of NSW spokeswoman said the crash occurred at 4.25 pm, and that initial reports suggested a truck had rolled over.
The Transport Management Centre confirmed that a truck was involved in the incident, and that bus services were affected by the five-vehicle smash.
A spokeswoman for the centre said people shoild avoid the area.
"The highway remains closed in both directions at the intersection with Holbeach Avenue, and there are significant delays in the area," she said.
"Motorists already travelling northbound on the Princes Highway should use Wickham Street and Marsh Street instead. Southbound motorists should use Canal Road and Gardeners Road."
Paramedics are still at the scene and have not yet taken anyone to hospital.
A recovery vehicle is on its way to the scene.
Route 348, 418 and 422 buses will start and terminate at Sydnenham because of the smash.