The fire was reported just before 7 p.m. in the 13700 block of Sproule Avenue.
Four people were already out of the home before firefighters arrived and saw the house engulfed in flames.
A 17-year-old boy and a 19-year-old man suffered burn injuries and were transported to the hospital in grave condition, said Los Angeles Fire Department spokesperson Katherine Main.
A 21-year-old man was also hospitalized in serious condition, and another man received non-life-threatening injuries, said Main.
The cause of the fire remains under investigation.
City News Service contributed to this report.