Chicago police said the crash happened at about 5 a.m. in the Little Village neighborhood near West 26th Street and South California Boulevard. That's near the Cook County Jail and the George N Leighton Criminal Courthouse.
All of the victims are adults, and the two people who have died were passengers in the vehicles involved in the crash.
Police on Sunday morning said one person was taken in serious condition to Mount Sinai Hospital, where they were pronounced dead.
Three other adults were initially transported to Stroger Hospital in serious condition, the Chicago Fire Department said. Police said later Sunday afternoon that one of those victims was pronounced dead.
A 37-year-old woman, who was driving one of the vehicles, is listed in serious condition, police said. Another person, identified only as male, is listed in critical condition.
What led up to the crash was not immediately clear.
"The way it sounded, I thought someone had hit the building," neighbor Edquinette West said.
The early morning collision is a sound residents who live at the Lawndale Garden Homes will never forget.
"Just metal crushing... loud, loud metal crushing," neighbor Gwendoyln Baldwin said.
Neighbor Andre Stewart noticed the driver of the silver KIA SUV was trapped inside. He and another person tried to rescue her by breaking the front windshield. Stewart said the victim was wearing a Chicago Police Department uniform. CPD would not confirm if she is an officer.
"All I heard is 'boom!' Just like that... that is when is started walking around this way, it was like a big old boom sound, like something had blew up," Stewart said. "There is a lady in there, the other guy looked behind me and said she is still breathing that's when we picked up some of the stuff from the accident and stating beating on windshield to get in the car."
Stewart said the fire department arrived just in time and finished the job. The 37-year-old female KIA driver was taken to Stroger Hospital.
Baldwin said crashes caused by speeding on 26th Street are common at the intersection.
"They recently added those cameras, but the camera is not going to stop anyone from speeding," Baldwin said.
After hearing the crash, Baldwin called 9-1-1. She said iron fencing was put up to protect their homes, and just four months ago concrete bollards were put in place to protect their vehicles from accidents at the corner of 26th & California.
"For the residents' protection, and it worked. My car is okay," Baldwin said.
Authorities did not immediately provide further information about the crash.