At least 100mm of rain has already been recorded in the northern Goulburn-Broken catchment and State Emergency Service officials warn those in western and central regions are also at risk of serious impact.
Watch and act alerts are issued for major flooding on multiple river systems including the Campaspe in Central Victoria, Ovens and King rivers in northeast Victoria.
In the 24 hours to 8am on Thursday, 40mm to 80mm were recorded in the Campaspe catchment, with up to another 100mm forecast throughout the day.
State Emergency Management Commissioner Andrew Crisp said the heavy rain would reach metropolitan Melbourne on Thursday afternoon.
"We've had nearly 30mm of rain in the last 24 hours. We'll probably see another 20 to 25mm on top of that," he told the ABC.
The SES has received more than 400 calls for help, mainly in Swan Hill, Echuca and Seymour.
"In the last 12 hours we've had 452 total requests for assistance, the majority of those are for floods followed by trees down," a spokesperson said.
Officials have been doorknocking along the Maribyrnong in inner Melbourne to ensure residents are on high alert, and search and rescue teams remain on standby.
Residents are also warned of power outages amid rising flood waters, fallen trees and debris.
The State Control Centre, which manages state emergencies, said 1211 properties are without power.
Sarah-Jane Gill, a manager at the Rochester Riverside Holiday Park in rural Victoria, has been evacuating guests and said she could see the river rising from her home.
"It is scary. You laugh in the face of it all but we're very nervous," she told AAP.
It comes after heavy rain caused a landslide near Falls Creek on Wednesday.
The slow-moving active slip forced the closure of Bogong High Plains Road at midday, with anyone left in the area told they might not be able to leave for three days.
Only emergency and essential service workers can access Falls Creek or Bogong Village and the main road won't reopen until the threat has passed.
Most of Victoria has been warned about wild weather and flash flooding on Thursday, with the worst set to hit in the afternoon and evening.
Communities near rivers, creeks and low-lying areas in the state's north are urged to stay on alert and up to date with warnings.
Damaging gusts up to 110km/h are tipped to hit alpine peaks on Thursday and clear from Friday morning.
Moderate flood warnings have been issued along the Avoca, Loddon and Murray rivers.
With large downpours expected, Premier Daniel Andrews reminded people not to drive into flood waters.
"It's dangerous for you and it's really dangerous for the person who has to come and rescue you," he told reporters on Wednesday.
Wildlife Victoria has initiated emergency response plans, anticipating an influx of calls for help.
The group doubled the number of emergency operators on shift on Wednesday night in a bid to cope.
Wildlife is particularly vulnerable in spring, with many animals caring for offspring.
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