Fire crews arrived at the home in the 400 block of Grenadine Street at around 10 p.m. Wednesday after neighbors called for help.
The neighbors had extinguished a fire on a fence, but flames were burning through home's roof, and firefighters entered through the front door to better attack the blaze, Rodeo-Hercules Fire Chief Charles Hanley said.
They quickly discovered roughly 80 marijuana plants growing inside, as well as unmarked containers of an unknown substance, Hanley said.
Fire personnel called in a county hazardous materials team to help handle the potentially dangerous material, and firefighters moved outside again for safety reasons.
Hanley said the blaze caused an estimated $325,000 in damage to the home and its contents, but caused no injuries.
The home's residents were nowhere to be found during the fire, and police and hazmat personnel are now investigating the marijuana grow and unknown substance found.