There are evacuation orders for Paradise, Magalia, Concow, Butte Creek Canyon and Butte Valley.
Firefighters had hoped to stop the fire's march south at the wide expanse of US 101, but it jumped the freeway as the region's notorious Santa Ana winds spiked in the early morning hours.
However there were no immediate reports of deaths or serious injuries.
Fire officials said strong Santa Ana winds continued to fuel the Woolsey Fire overnight, doubling its size to almost 3,248 hectares. Evacuation orders in the Hidden Hills area of Los Angeles County were also downgraded to voluntary.
State officials are investigating electrical equipment as one of several possible causes of the fire in the north, said Scott McLean, a spokesman for Cal Fire, in an interview.
The entire city of Malibu was ordered to evacuate as the Woolsey Fire, as it has been named, continues to get closer to residential buildings.
The hospital was totally destroyed, Mike Mangas, a spokesman for operator Dignity Health, told Action News Now. Investigators found the five people in the area of Edgewood Lane in Paradise inside of cars.
More than 400 firefighters from Ventura County, Los Angeles County, the City of Los Angeles and Cal Fire were battling the brush fire.
Ventura County Fire Department clarified on Twitter that Los Robles Hospital was not being evacuated. The speed of the fire caught everyone off guard as it was driven forward by the high winds and dry landscape. consuming more than 28 square miles (73 square kilometers) by nightfall with firefighters unable to contain any of the blaze, McLean said.
Wildfire triggers evacuation order for Malibu
Director Guillermo del Toro tweeted that Bleak House, his museum of horror movie memorabilia, was also in the path of the flames. In total, there are now 14 wildfires blazing in California and acting governor Gavin Newsom has declared a state of emergency .
"We've spoken to our pastors, and they're all safe, and as far as they know, so are their congregants", says Bret Allen, district superintendent for the Northern California and Nevada district.
No estimate was given on the number of structures destroyed but the Fire Department did say there were "many". "People were abandoning their cars and running with their babies and kids".
The blaze, which spewed massive plumes of thick black smoke, also threatened parts of the nearby town of Thousand Oaks, where a gunman killed 12 people earlier this week in a shooting rampage at a college bar, stunning the bucolic Southern California community with a reputation for safety.
With three fires burning around Southern California, state officials believe about 157,000 have been displaced.
The blaze that started Thursday morning east of Paradise and decimated the town also spread to the west.
At least 200 deputies will be in the five Los Angeles County cities effected by the fire - Westlake Village, Hidden Hills, Agoura Hills, Calabasas and Malibu - doing property evaluations and looking for any possible looters, Los Angeles County Sheriff's Department Chief John Benedict said.
Several evacuation centres were issuing protective masks for citizens, Ventura County Emergency Services said, and many schools remain closed. The fire reportedly jumped Pacific Coast Highway about 10 p.m. Friday, moving toward Malibu Colony.
Despite evacuations in Malibu and flames threatening near campus, Pepperdine University called for students and staff to shelter in place.
As of Sunday evening, the entire city of Calabasas is now under mandatory evacuation orders. "This is a very risky wind-driven fire".