Rare mid-May snowflakes are possible overnight and early Tuesday across some of the higher elevations of Western New York, the National Weather Service said.
Metro Buffalo will be spared but more rain, patchy fog and temperatures 15 to 20 degrees below normal are expected.
The chilly, damp weather is being generated by a core of cold air associated with low pressure tracking across the region.
It's unlikely snow will accumulate in the Buffalo Niagara region, but it could happen in other parts of the state.
"The best chance for any measurable snow will be east of Lake Ontario across the Tug Hill, where a few tenths, up to an inch, will be possible," the weather service said.
It added: "A few wet snowflakes may also mix in across the higher terrain south of Buffalo."
Forecast models suggest accumulating snow is also likely across the Adirondacks, northern New England and in Vermont and New Hampshire.
In metro Buffalo, overnight lows are expected to dip to about 40 degrees with periods of rain forecast. Up to one-quarter inch is possible.
Rain is expected to continue Tuesday with some patchy fog likely in the morning. Tuesday's high is forecast around 50 degrees.
Buffalo's latest measurable snowfall on record was 0.1 inch on May 20, 1907, weather service records show.
The city's average high daily temperature for this part of May is 66 degrees.