The three-alarm blaze started about 2 a.m. in the former brewery's bottling plant, which dated back to the 1890s.
Firefighters subdued it within a few hours, but a hook-and-ladder crew was still spraying water on hot spots in the late morning.
No injuries were reported in the fire, which was first spotted by a security guard.
Cause of the fire was not immediately known. Arson investigators will search for clues once the fire is extinguished.
Randy Jenkins, a fire department spokesman, said flames were shooting through the roof of the 40,000-square-foot structure by the time fire crews arrived at the scene.
Heat from the fire also ignited a smaller fire in the neighboring brewhouse, a gold-domed landmark along the San Antonio River that is being redeveloped.
Jenkins said a precise assessment of damage to the brewhouse wasn't available midday Thursday, but he said it looked to be limited to one or two rooms.
The Pearl Brewery, one of the state's largest, was closed in 2001 after more than a century of operation.
The Pabst Brewing Co., which had owned Pearl, used the brewhouse as its corporate offices until its sale to a local development group in 2002.
The fire was the second at the brewery in the past year. The previous fire, caused by a welding spark in early November, caused little damage inside the brewhouse.
