Officials said the blaze had consumed at least 800 acres as of 11 a.m. EDT and had a "dangerous rate of spread."
The fire remains completely uncontained, according to the agency.
The Napa County Sheriff's Office said mandatory evacuations were ordered on Silverado Trail, Lark Mead Lane to Deer Park Road as well as from Deer Park Road to Devils Elbow.
Parts of the community of Angwin were also under evacuation orders. Officials were urging people in Angwin to evacuate because their evacuation route could become blocked.
One resident on Crystal Springs Road told KTVU she could hear propane tanks exploding in the distance and believed the fire was burning in an area with homes and wineries.
Authorities have not said if any structures have burned, but at least six wineries are located within the evacuation zone, according to KTVU.
Patients are being evacuated from St. Helena Hospital, according to the Contra Costa County Fire Protection District. Adventist Health St. Helena said on Facebook it is "temporarily suspending emergency and hospital care, and all patients will be transferred," because of the fire.
The sheriff's office warned those evacuating from the area to not stop or park in turnouts to view the fire.
"First responders often need access to the turnouts to park emergency vehicles. Please allow first responders to do their jobs," police said.
Napa County officials are opening an evacuation center at Crosswalk Community Church on First Street in Napa as Cal Fire teams from San Mateo and Santa Cruz Counties were called in for assistance.
California is facing a new stretch of hot, dry weather with potentially strong winds that could cause power lines to arc and spark new blazes in parched vegetation that’s ready to burn.
The state's largest utility, Pacific Gas and Electric Company (PG&E) said Saturday a Public Safety Power Shutoff (PSPS) will begin early Sunday morning and impact 89,000 customers overall in portions of 16 counties and a tribe.
Red Flag warnings for extreme fire weather conditions are in effect in northern and central areas of the state at 9 p.m. Saturday and last into Monday, according to the National Weather Service (NWS).
More than 8,000 California wildfires so far this year have scorched 5,600 square miles, destroyed more than 7,000 buildings, and killed 26 people.
The renewed concern of weather igniting new blazes came with some 17,000 firefighters still on the lines of 25 major wildfires statewide, according to Cal Fire.
The Associated Press contributed to this report.