The six-vehicle accident occurred just after 6.45am, closing all northbound lanes plus two of the five southbound lanes on the bridge.
Emergency crews cleared the accident by 8am but all roads approaching the CBD have been affected causing peak-hour chaos for commuters.
Motorists have been urged to take the ferry or train.
Two people were hurt in the accident and have been taken to hospital, an ambulance spokesman said.
One patient is in a serious condition and has been taken to St Vincent's Hospital, while the other is going to Royal North Shore
with minor injuries, he told AAP.
Transport Management Centre is advising motorists to expect significant delays throughout the morning's peak rush.
Citybound buses that normally travel over the Sydney Harbour Bridge are dropping passengers at North Sydney train station, with some buses are delayed up to one hour.
Citybound buses using Victoria Road and the Anzac Bridge are also delayed up to one hour due to heavy traffic.
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