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.
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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.
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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.