CFD Deputy Chief John Giordano said roughly 100 firefighters responded to a three-story building in the South Shore neighborhood's 6700-block of South Crandon Avenue around 4:20 a.m.
There, firefighters battled heavy flames on the first and second floors of what residents say is a family-owned building.
A mayday was called for a missing firefighter, who was located quickly, said CFD Deputy Chief John Giordano.
Chicago police said crews rescued a 16-year-old boy and a 53-year-old woman from one of the units.
One man told ABC7 that the two are his nephew and sister. Police and fire officials said they were transported to the University of Chicago Medical Center in critical condition, and relatives later told ABC7 that they are now stable.
Meanwhile, one firefighter was taken to a local hospital for a minor injury.
Giordano said the fire appeared to have started in a second-floor living room before spreading to the first and third floors, and the building is a total loss.
CPD said four other people, in addition to the two rescued, were displaced.
CFD is investigating the cause of the fire.
ABC7 cameras were on the scene, where crews could be seen focusing on hot spots around 5:30 a.m. Firefighters had left the scene by 8 a.m.
Authorities did not immediately provide further information.