The fire was reported just after 3:30 a.m. Saturday morning in the 2100 block of South Lamar, behind the restaurant Loro and near West Oltorf Street.
People on social media posted photos and videos of the fire, which prompted a brief road closure while first responders worked to extinguish the flames.
The fire fully engulfed an unoccupied, two-story building, and damage is estimated at $4 million.
No person of interest has been named and the investigation remains ongoing as of Tuesday evening, the agency said.