There were no injuries reported but firefighters rescued four snakes from the property.
The fire was reported around 12:45 a.m. at the Vista Village Center in the 25800 block of Tournament Road.
When firefighters arrived, flames were already visible through the roof and they declared a second alarm to bring in more resources.
Ultimately firefighters contained the damage to four out of the strip mall's 10 units, several of which had to be bulldozed for safety.
The fire was declared a knockdown shortly after 2 a.m.
Firefighters rescue snakes after fire burns through stores at Santa Clarita strip mall
Businesses damaged by fire included a dry cleaners, a church, a dentist office and a store called The Olde World Apothecary & Botanica that specializes in items and classes associated with witchcraft and occult interests.
Firefighters bulldozed Olde World and Village Cleaners. Video during the firefight showed the flames apparently concentrated at the back of those two businesses.
They rescued four nonvenomous snakes, though it was not immediately clear where they came from.
"This was a pretty dangerous situation," said Fred Fielding, a spokesman for the Los Angeles County Fire Department. "There was extensive fire throughout. Not only are we trying to make sure the building is being saved as much as possible but that we're taking into account the safety of the firefighters."
The cause of the fire remains under investigation.