The crash occurred at about 1:48 a.m. in the 400-block of North Lake Shore Drive.
Police said a black SUV with two men inside was going northbound in the southbound lanes when it struck a white SUV, which then struck a white sedan.
Both men in the black SUV and two adults in the white sedan were transported to hospitals, where they were listed in serious condition, police said.
The crash occurred in the area where the DuSable Lake Shore Drive bridge malfunctioned, but it is not believed to be related to the crash.
Further details were not immediately available.