Palo Alto fire got the call around 7:15 p.m.
They arrived at the home on Embarcadero Road to find half the residence fully involved. They also found two bodies inside.
The investigation into the deaths will be handled by Palo Alto police, fire and the Santa Clara County Arson Task Force.
"Any time there's a fatality at a fire scene, we'll put up a crime scene until we're able to determine what exactly happened, if the fire was criminal in nature or not," said Palo Alto Police Lt. Zach Perron. "That's a routine investigative step. It happens at every fire when we discover a body."
A next door neighbor says a man and his caretaker lived inside that home.
"Donnie was a Vietnam War vet and I think he's been pretty sick cause I haven't seen him in a while," neighbor Mike Kelly.
Firefighters did have some trouble putting out the fire because there were a lot of items inside the home like newspapers and boxes.
"We had a hard time getting in and where we needed to go," Palo Alto Fire Department Deputy Chief Catherine Capriles said. "The home was apparently in fairly poor condition before the fire began so the fire just enhanced that and made it worse."
The investigation will get fully underway on Saturday.