The blaze started on Friday and spread rapidly on Saturday, forcing the closure of a major road and the evacuation of about 730 homes in northwest Los Angeles and nearby Burbank and Glendale.
Mayor Eric Garcetti said the fire had already burnt 5,000 acres (2,000 hectares), adding: "In terms of acres involved this is probably the largest fire in LA city history."
Los Angeles Fire Department Chief Ralph Terrazas said the area's last fire was at least 30 years ago and agreed that the current blaze was the largest in the city's history.
Late on Saturday afternoon local time, he said firefighters were dealing with "very erratic weather and wind".
"Our biggest concern is the wind and weather," he said.
"The erratic weather is our number one challenge.
"If there's no wind, this is a relatively easy fire to put out.
"But when the wind changes, it changes our priorities because other properties become at risk."
But strong winds are forecast, with temperatures expected to climb into the late 30s.
More than 500 firefighters are trying to control the fire and 100 others, who were sent to Houston to help that city through flooding, have been called back to California.
There have been no deaths or injuries reported and, despite the fire's size, only three houses have been destroyed.
There are concerns that the fire could make it difficult for people to breathe in Los Angeles, the country's second-largest city, according to a warning from the South Coast Air Quality Management District.
Meanwhile, 400 miles north, the Ponderosa Fire has burned 3,880 acres and destroyed 30 homes in Butte County since Tuesday.
Around 500 homes were evacuated due to the blaze, which grew from a camp fire and is now 45% contained.
A man has been charged with two counts of arson.
Wildfires are also raging in other states, including Montana, Oregon, Washington, Wyoming and South Dakota.