The crash happened at 4:45 p.m. at the intersection of Pike Street and Boren Avenue.
Witnesses told police the bus was heading eastbound on Pike when a van traveling northbound on Boren ran a red light and hit the front corner of the bus.
Two people in the van -- the male driver and female passenger -- were taken to nearby Harborview Medical Center with life-threatening injuries, according to police.
A woman on the bus was also taken to the hospital with non-life threatening injuries.
The crash temporarily blocked traffic in the area and rerouted several downtown bus lines, including the 10, 11, 43, 47 and 49.
There were no citations issued at the scene, which police say is standard procedure in serious crashes that require extensive follow up investigation and collision reconstruction.
Traffic Collision Investigation Squad detectives responded to the scene and continue to actively investigate