CBD residents along with those in surrounding Lismore Basin, East Lismore and Girards Hill have been urged to leave immediately.
"Everything's falling apart in Lismore at the moment," Lismore Mayor Steve Krieg told the Nine Network on Wednesday morning.
"Our river is normally about eight metres lower … We're estimating in about half an hour to an hour that's going to come up over the levee and the Lismore CBD … will be inundated with water again.
"So, second time in a month."
"I'm going to jump in my car and get to higher ground."
The Wilsons River is expected to burst its levee, hitting major flood levels of 10.6m.
The worst could be yet to come with further river rises at Lismore still possible on Wednesday afternoon.
Byron, the owner of a petrol station in Murwillumbah said his business was flooded in the last catastrophic event in the Northern Rivers.
"It came up to like two metres (high) in the shop and we've lost everything," he said.
The most recent floods had broken the business' petrol pumps, ovens and fridges which had all since been replaced.
The evacuation order is the second for the city in 24 hours after an all clear was issued to return with caution on Tuesday afternoon.
Some six evacuation orders are in place across NSW for areas including the Lismore CBD, Lismore Basin, low lying areas of East Lismore, North Lismore and Girards Hill, Riverside Caravan Park Coraki, Tumbulgum, Low lying parts of Kyogle, parts of South Lismore and Bellinger River Tourist Park on the north coast.
Flash flooding in the CBD as a result of heavy rainfall has inundated roads and an evacuation centre has again been set up at Southern Cross University.
Another bout of flooding could seriously affect those in the middle of a long clean-up from the recent flooding catastrophe, University of Sydney mental health professor James Bennett-Levy told AAP on Tuesday.
"There is extreme distress because what it does is re-trigger and re-traumatise people who have already been severely traumatised."
Dr Bennett-Levy, who directs the Centre for Rural Health in Lismore, said "very high levels" of post-traumatic stress disorder are expected.
"It is not just people directly affected, there is collective trauma because just about everyone in the community knows ... multiple people ... whose houses have been inundated," he said.
In a study conducted after the 2017 floods, Dr Bennett-Levy along with other researchers found 50 per cent of people displaced for more than six months in the same region had PTSD.
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