11:25AM UPDATE: The Axedale-Goornong Road remains closed to traffic.
City of Greater Bendigo Emergency Response Officer Nigel Scarff said the road would be re-opened within an hour.
State emergency services, Axedale police and council workers were at the crash site, clearing the scene.
A neighbouring paddock took in live or injured sheep.
Axedale Police Leading Senior Constable Laurie Mueck said the injured sheep would be shot.
"We will assess the live-stock for broken bones," he said.
"Those injured will be humanely destroyed."
7:45AM: BENDIGO police put down 350 sheep after a semi-trailer carrying livestock overturned and caught fire on Sunday night.
Bendigo Highway Patrol Sergeant Peter Beaman said many sheep were still roaming the roadside on Monday morning.
The B-double sheep transporter was carrying 800 sheep when it rolled on Axedale-Goornong Road about 9pm. The driver and passenger escaped before the vehicle caught fire.
Bendigo Fire Station Officer John Lane attended the incident and said the blaze took about 30 minutes to control.
"Three fire trucks attended, with extra CFA tankers providing water," Mr Lane said.
He said hundreds of sheep perished or were injured in the inferno.
Ambulance Victoria spokesman Paul Bentley said an ambulance was called to the scene and a female passenger in her 20s was treated for cuts.
"She was taken to Bendigo Hospital in a stable condition," he said.