Emergency warnings have been issued for Rochester along the Campaspe River, Carisbrook near Maryborough, and Seymour along the Goulburn River, directing residents to immediately evacuate.
Major flooding is expected to inundate the Rochester area on Friday from 10am, with the river to peak in the afternoon.
An evacuation centre opened at the Echuca United Football Netball Club, and relief centres have been set up at Maryborough Sports and Leisure Centre and Seymour Sports and Aquatic Centre.
Emergency warnings have also been issued from Seven Creeks to Euroa and for the Campaspe River between Lake Eppalock and Barnadown.
Anyone in low-lying areas or close to a waterway has been told they are in danger and should move to higher ground immediately.
Authorities expect Shepparton to experience its worst flood in almost three decades on Saturday afternoon, with up to 600 properties isolated.
The State Emergency Service has received more than 1600 calls for help and 10,000 people have been left without power since the wild weather began on Wednesday.
The SES rescued 30 people by Thursday afternoon, including those driving through floodwaters in rural areas. No serious injuries have been reported to date.
Victorian SES Chief Operations Officer Tim Wiebusch said Seymour was facing its highest flood level since 1974.
"There is the potential for 187 properties to be inundated by floodwaters and a further 279 properties that could be isolated," he told reporters on Thursday.
Echuca residents have been advised to boil drinking water until further notice after stormwater entered a storage tank.
Watch and act alerts have been issued for major flooding of multiple river systems, including Ovens and King rivers in northeast Victoria.
The Thompson Dam in Gippsland could overflow by the weekend and other catchments which have not spilt in decades are flooded.
Central and northern Victoria experienced the worst of the downpour, with more than 160mm recorded at Strathbogie and 145mm near Euroa.
The rains caused landslides at Separation Creek on the Great Ocean Road on Thursday and at Falls Creek in the alpine region on Wednesday.
Authorities are bracing for up to 700 properties in Rochester to be isolated by Friday and about one third of those to have flooding above floor level.
Sarah-Jane Gill, a manager at the Rochester Riverside Holiday Park in rural Victoria, evacuated 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.
Rochester cafe owner Lisa Froon feared water would seep through her premises but chose to remain open to provide food to locals.
"I had some tears last night," she said.
A relief centre has been established at Echuca to support evacuated residents.
In 2011, a record flood hit the town of Rochester after the Campaspe River reached a historic peak of 9.12 metres.
Bendigo Mayor Andrea Metcalf said the area was bracing for the severe flooding in Rochester to flow downstream, with several of its football and soccer fields already inundated by Thursday morning.
About 40 schools and early childhood learning centres across the state, including Seymour College and Kilmore's Assumption College, closed on Thursday.
Regional transport has also been impacted, with buses replacing trains between Albury and Seymour in both directions and all Melbourne-bound lanes of the Hume Highway closed between Benalla and Avenel.
34°C