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Authorities in Orange County said they were dealing with a "bus rollover", describing it as a "mass casualty" incident.
New York State Police said it was a "serious bus crash with multiple serious injuries".
There were about 45 people on board, mostly children, Orange County Executive Steve Neuhaus told WNBC-TV.
At least five people were badly hurt, he added.
It happened on Interstate 84 in the US town of Wawayanda, around 75 miles northwest of New York City, police said.
It is unclear what caused the crash and the weather was clear at the time.
The bus was one of six carrying members of a high school band from Farmingdale, New York, to a band camp in Greeley, Pennsylvania, according to a statement from the Farmingdale School District given to local media.
Video from helicopters showed the vehicle lying on its side in trees and shrubs, several yards off the road.
A ladder enabled rescuers to reach the windows.
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Footage also showed a logo for Regency Buses, which serves New York, New Jersey and Connecticut.
The highway was closed at exit 15a for an accident investigation, New York State Police said.
"I have been briefed on the tragedy in Orange County where a bus filled with high school students was involved in an accident, leading to injuries and one fatality," New York Governor Kathy Hochul said in a statement.