Firefighters responded around 6:45 p.m. to two structure fire alarms, one reporting burnt food, at 333 G St., according to the fire department.
The Bradford House, a historic structure built in 1863 and currently used as a multi-occupancy residence, was found engulfed in flames, fire officials said.
Flames on the exterior of the house were traveling up toward the attic, and second, third and fourth alarms were called by 7:50 p.m., according to the fire department.
Small hidden spaces within the building made access difficult and dry heat fueled the blaze, fire officials said. Firefighters were able to contain flames to the upper floor and attic and attempted to save the building's contents from additional smoke and water damage.
Loss was estimated at more than $350,000, according to the fire department.
San Rafael fire crews were assisted by fire agencies in Novato, Marinwood, Marin County, Kentfield, Southern Marin, Mill Valley, Ross and Ross Valley.