There were no immediate reports of deaths, and three people were taken to hospitals.
The four-lane Interstate 5 bridge more than half a century old collapsed about halfway between Seattle and Vancouver, British Columbia, Trooper Mark Francis said.
Francis said he did not know what caused the collapse, which came at the start of one of the country's busiest holiday weekends of the year.
Xavier Grospe, who lives near the river, said he could see three partially submerged cars, and the apparent drivers were sitting either on top of the vehicles or on the edge of open windows. "It doesn't look like anybody's in danger right now," Grospe said.
The collapse came before sundown on a clear day. Helicopter footage aired by a television in Seattle showed one rescue boat leaving the scene with one person strapped into a stretcher. A damaged red car and a damaged pickup truck were visible in the water, which appeared so shallow it barely reached the top of the car's hood.
Kari Ranten, a spokeswoman for Skagit Valley Hospital, said two people who were injured in the collapse were en route to the facility. She said another person was being taken to a different area hospital.
A man told the local Skagit Valley Herald newspaper he felt a vibration and looked in his rear view mirror to see that the part of bridge he had just crossed was no longer behind him. "I thought something was wrong with my car at first," he said.
The collapse will raise questions about the state of the nation's infrastructure, which has been a popular issue with President Barack Obama, who earlier this year warned against "raggedy" roads and wants to focus more money on rebuilding to improve the economy.
The American Society of Civil Engineers' 2013 infrastructure report card gave the country a dismal grade of D-plus overall. The bridge that collapsed Thursday is not considered structurally deficient but is listed as being "functionally obsolete" meaning that its design is outdated, according to a database compiled by the Federal Highway Administration.
The bridge was built in 1955 and has a sufficiency rating of 57.4 out of 100, according to federal records. That is well below the state-wide average rating of 80, according to an Associated Press analysis of federal data.