Crews responded to the blaze, at 1020 S. 7th St., at about 9:30 p.m. Monday and found huge flames billowing from the roof and upper windows.
Fire officials say the house had been vacant for some time, but homeless people may have been living inside.
The blaze started on the second floor, and crews were able to prevent the flames from spreading to other nearby homes.
No one was hurt.
The fire remains under investigation.