As it neared Ronald Reagan National Airport in Washington, DC, an American Airlines aircraft carrying scores of passengers crashed with a military helicopter.
Boats and divers are looking for survivors in the water after the jet fell into the Potomac River, according to officials.
Around 21:00 EST (02:00 GMT) on Wednesday, the helicopter was nearing the runway when it collided with the Bombardier CRJ700 regional plane, which was carrying 60 passengers and four crew members.
The plane was coming from Wichita, Kansas, according to the airline.
The crashed plane has split in half in the Potomac River with boats and divers now searching for people, US media reports say.
Three US army soldiers were onboard the Black Hawk military helicopter that collided with the jet, a defence official said.
The helicopter had taken off from Fort Belvoir in Virginia.
US President Donald Trump said he had been "fully briefed on the terrible accident".
"Thank you for the incredible work being done by our first responders. I am monitoring the situation and will provide more details as they arise," he said in a statement.
Takeoffs and landings have been halted at the airport as emergency personnel respond to the incident, the airport wrote in a post on X.
The Federal Aviation Administration said it was conducting an investigation.