The fire broke out around 9:45 a.m. Saturday in the 5200-block of South Lorel, officials said.
PHOTOS: 2 killed in Garfield Ridge fire
"Fire marshals are bringing the fire dogs in for their investigation," said Chicago Fire Department Chief Paul Foertsch.
Liliana Almazan shot cellphone video of the flames from her porch just moments before the fire department arrived on-scene. Residents say the house was entirely consumed in a matter of minutes.
"It was kind of scary because people were screaming, 'Is there anyone in the house? Is there anyone in the house?'" Almazan said.
"It started in the back. And then all of a sudden, everything exploded inside," said Magda Garcia, a witness.
The fire department says the victims are two men; one a 63-year-old man who owned the house. The second was a 28-year-old who had been staying there for about a week.
"The victim on first floor was in a rear bedroom. The victim on second floor was found near a window," Foertsch said.
Family members say the 63-year-old was Saide Jodie, a longtime employee of the Post Office who never married or had any children.
Police haven't confirmed details but say the younger of the two victims had an extensive criminal background.