The fire was reported shortly before 3 a.m. in the 500 block of Lincoln Boulevard, according to the Santa Monica Fire Department.
Firefighters arrived to find heavy flames on all sides of the home, and a car parked in the driveway indicated that residents were possibly inside.
Two people were found during a search and were pronounced dead at the scene. They were not immediately identified.
Neighbors told investigators that an elderly couple and a caretaker live at the house.
The cause of the fire was unknown.