At about 4 a.m., a white Infinity sedan was travelling westbound in the 4000 block of West 26th Street ran a red light and hit the bus, according to police.
The #53 bus was travelling northbound and ended up crashing into a building, police said.
The 18-year-old driver of the vehicle was transported to Mt. Sinai Hospital where he later died, police said. His 21-year-old female passenger was transported to Mt. Sinai in good condition.
Both the female bus driver and a female passenger were taken to the hospital in good condition.
Amparo Galan said she had boarded the bus a couple of blocks earlier to get to work.
"I had just closed my eyes when the accident happened," she said. "I went flying from my seat. I hit myself in the corner of the other seat, right here, really hard, here in my ribs."
Video from the scene shows extensive to damage to the building, and the bus and vehicle involved in the crash.
The building partially collapsed as crews removed the bus from the scene.
WATCH: CTA bus pulled from crash site
People watched as part of the exterior of the building came crumbling down.
"Around here, all the buildings are kind of old, so they kind of collapsed," resident Nacho Hernandez said. "So by a car hitting it and going down... I don't expect that."
People walking by found pieces from the vehicles involved scattered across the congested intersection, and they were in utter disbelief.
"The impact had to be so devastating, so big where it just blew it off across the street," resident Alfredo Bahena said. "The person had to be fast. This is an alternator that came from under that hood there. To be at this distance, it had to be the velocity had to be pretty high."
No citations have been issued at this time and no other information is available, according to police. Officers continued to help control traffic while demolition crews cleaned up debris.