The crash occurred at about 12:40 a.m. on the 3000-block of South DuSable Lake Shore Drive.
A Honda sedan was traveling in the wrong direction of DuSable Lake Shore Drive when it struck a Ford Expedition, police said.
The male driver and female passenger in the Honda were both transported to the University of Chicago Medical Center in critical condition, police said.
The male driver of the Ford Expedition was transported to Northwestern Memorial Hospital in fair condition, police said.
No other injuries were reported and the Chicago Police Major Accidents Unit is investigating the crash.
INTERACTIVE SAFETY TRACKER Track crime and safety in your neighborhood