The bus, carrying students from Farmingdale High School in Nassau County on Long Island, was headed to band camp in Greeley, Pennsylvania.
The crash happened westbound on I-84 in Wawayanda at 1:20 p.m.
There were 40 students and four adults on board the bus at the time of the crash.
Two adults, 43-year-old Gina Pellettiere and 77-year-old Beatrice Ferarri, were killed. According to the Farmingdale High School's website, Pellettiere was the school's band director.
Five students were also critically injured, State Police Lt. Col. Richard Mazzone said.
The person killed in the crash is believed to be an adult. The five passengers who were critically injured are all believed to be juveniles.
Victims were transported to both Westchester County Medical Center and Garnet Health Medical Center in Wallkill.
Injured students from bus crash taken to 2 hospitals
Westbound lanes were closed at exit 15 for the investigation. New York State Police said the highway was expected to be closed for several hours.
State officials said all children who were on the bus have been accounted for. A heavy-duty vehicle arrived at the scene to tow the crashed bus away.
The injured students who did not require hospitalized were being taken to to a community building for reunification with parents.
The bus, owned by Regency Transportation in Nesconset, was one of six in a caravan carrying students from Farmingdale High School.
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Students on the other buses were to stop off at a community college for a break and meet with counselors before heading back to Long Island.
Gov. Kathy Hochul released a statement on the tragedy, saying, "We are grateful for the first responders whose speedy action saved lives and we will continue to support them however necessary. Our hearts are with all who are impacted by this horrific situation."
Students and faculty members at Farmingdale High School were were shaken following the tragic events that unfolded on Thursday.
"My niece is on one of the other buses, she's okay. It's terrifying," Howitt Middle School teacher Donna Baltch said. "These kids go on a trip to have fun, this is something that they look forward to all year, and these poor teachers, these chaperones, I'm hearing mixed things, we don't know if they're okay. Right now, we are just praying and hoping that they're okay."
Tragic bus crash shakes students, faculty at Long Island high school
The NTSB, in coordination with the New York State Police, is sending a team to conduct a safety investigation into the crash. The team will arrive at the scene on Friday morning.
This story will be updated when more information is available.