TV footage showed an amphibious “Ride the Ducks” vehicle smashed into the side of the bus on Aurora Bridge.
The four victims were foreign students from North Seattle College. Several people were critically injured.
Seattle Mayor Ed Murray described the crash as “a terrible tragedy”.
The tragedy happened at about 11:00 local time on September 24. Two smaller vehicles were also involved in the crash.
Most of the victims were on board the charter bus. Officials have not said which countries they were from.
Forty-five students and staff members from the school’s international programs were taking an orientation trip ahead of the school year starting on September 21.
Fifty-one people were taken to hospitals. Fire department officials said 12 had critical injuries.
“Today, the North Seattle College community learned devastating news that four of our students were tragically killed in a vehicle accident on the Aurora Bridge,” the school said in a statement.
“Additionally, several students remain in critical condition, and other students and a North employee sustained serious injuries.”
Government officials were working to contact next of kin.
A witness said the duck boat signaled to move left when it lurched and the front left wheel came off. It then clipped a vehicle before colliding with the bus.
Mayor Ed Murray said the company had voluntarily suspended trips for the time being.
“Ride the Ducks” tours, using vehicles which can drive on roads and float on water, are known for guides who play loud music and quack through speakers when leading tourist groups.
The amphibious vehicles have been involved in multiple fatal accidents.
Two people died when one collided with a barge in Philadelphia, Pennsylvania, in 2010.
The “Duck” name is derived from DUKW, the six-wheel amphibious vehicles used by the US military during World War Two.
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