It happened Monday morning at a one-story commercial building in the 6900-block of South Chicago Avenue.
The building housed a deli and a car wash.
Flames shot through the roof, which eventually caved in.
Several explosions were heard as firefighters tried to control the flames.
Fire investigators say electrical lines were the likely source of the noises.
"It could have been material inside the building. It was a car wash and other things. It could have been propane tanks and electrical. I heard electrical going off in there," said Dep. Dist. Chief Jim Mungovan, Chicago Fire Department.
The building is being called a total loss.
No injuries were reported.
There is no word yet on a cause.