Ministry staff are spending the day picking up dead birds that washed up on the shoreline in the Wasaga Beach area on the weekend.
Ministry spokesman John Cooper says initial estimates pegged the number of dead waterfowl as high as 6,000.
Cooper says previous die-offs often were caused by the waterfowl eating botulism-laced fish and tests are being done to determine the cause of this fall's deaths.
He says there was a die-off last autumn in the same region, but the numbers were in the hundreds and the large number this fall is unusual.
Officials say it's not a threat to human health, but residents are being warned to keep a tight rein on their pets.
Bottom-feeding fish ingest toxins that cause botulism and the birds feast on the dead or dying fish. Fish react to the toxin by becoming erratic, making them an easier prey target for a loon or duck that's looking for something to eat, Cooper said.
The die-offs along a roughly three-kilometre stretch on Georgian Bay is the largest Ontario officials have seen in many years. About a decade ago some 25,000 birds died on Lake Erie from eating botulism-laced fish.