Residents of the Northern Territory town of Katherine and nearby Beswick have been warned to move to higher ground if necessary and shelter indoors.
Katherine Mayor Joanna Holden said it was so wet "even the ducks have left town".
Northern Region controller James O'Brien urged residents not to panic, saying the town centre and main suburbs were not expected to be flooded but some homes in low-lying areas could be inundated.
NT Chief Minister Lia Finocchiaro on Friday announced an emergency declaration for the Big Rivers region, triggering the closure of government schools in Katherine and surrounding communities.
Three schools would be set up as emergency shelters with a capacity for 850 people, she told reporters in Darwin.
The Katherine River was expected to reach a flood peak of 17.5 metres on Friday afternoon, with sandbags being readied for residents to use.
About 34 patients were being evacuated from the hospital, with 21 to be flown out to other health facilities.
Mr O'Brien said sudden water rises had flooded roads, including part of the Stuart Highway, catching out two motorists who had to be rescued.
Major flooding was also expected at Daly River where the community had only recently returned after being evacuated due to flooding, he said.
Shenagh Gamble from the Bureau of Meteorology told reporters a monsoon trough across northern Australia was expected to bring more heavy rainfall over the next 24 to 48 hours.
Warnings were in place and a flood watch applied to most of the base of the Top End, she said, including a major flood warning for the Beswick community on the Waterhouse River.
Mr O'Brien said there had been panic buying in Katherine on Friday morning.
"I would urge Katherine residents, please remain calm ... we will always be able to get goods in there with our supply chain we've got at the moment."
Ms Holden told AAP residents were preparing for flooding, having woken up to the unexpected threat that remained unpredictable.
"It's quite damp, I think even the ducks have left town it's that wet," the Katherine mayor said.
"People have been stocking up at Woolworths and the local fruit and vege shop but that has subsided."
The weather bureau said two tropical low pressure areas were causing heavy rain and flooding in the NT and Queensland, with significant rainfall expected to continue into the weekend.
A tropical low pressure area close to Cairns is forecast to cross the coastline and move on to land by mid-Friday and head southwest towards central parts of Queensland then veer towards the state's southeast.
The system caused significant flooding north of Cairns through Port Douglas up towards Cooktown.
For Friday evening into Saturday morning it could be very wet over interior parts of North Queensland, senior meteorologist Angus Hines said, causing flash and riverine flooding.
Heavy rain was also predicted for Townsville to Mackay and the Central Coast area before spreading down the east coast on Saturday.
The densely populated southeast is on alert, with widespread falls of up to 150 millimetres expected over a 36-hour period between Saturday night and Monday morning, including in Brisbane.