The fire erupted just after midnight at a residential building in the 1000 block of W. Leighton Avenue, according to the Los Angeles Fire Department.
Firefighters searched through the residence and rescued two the man and woman. They were transported to a hospital, where the man was pronounced dead.
At least eight adults and four children were displaced by the fire, according to the fire department. Crews said the residence appears to be a board and care facility.
One resident said he and his roommate heard the smoke alarm, opened their door and were immediately hit by a plume of smoke.
"We slammed the door back, hit the floor - it was the only way we could breathe - covered our mouths with a towel and exited through the window. Didn't even take the time to open it. Thankfully, it was a 120-year-old pane of glass," Matthew Hogan said.
It took more than 50 firefighters about 40 minutes to contain the fire, officials said.
One firefighter was also hospitalized as a precaution for smoke inhalation.
The cause of the fire is under investigation.