The crash happened just after 1:30 p.m. at East Marginal Way S. (Highway 99) near S. Nevada Street, fire officials said.
One person was trapped in their car and it took several firefighters to free him. He was eventually loaded into an ambulance and taken to Harborview Medical Center where he was listed in serious condition, fire officials said.
Two others hurt in the crash were also expected to be taken to a local hospital with serious but not life-threatening injuries.
The road was closed to traffic for hours as police investigated and cleared the scene, causing significant backups in the area.
For more than five hours, a cascade effect of traffic paralyzed the city.
"I just want to go home and we're never gonna get home. We're about to run out of gas," one frustrated driver said.
Mariners PA announcer Tom Hutyler got stuck in the mess on his way to the game. He tweeted that it took him 93 minutes to drive from KOMO headquarters near Seattle Center to Safeco Field, which is less than three miles alway.
Around 7:30 p.m. SR-99 was reopened for traffic.