LAFD said firefighters responded to the 118-year-old church located at 1376 E 18th St. after the blaze erupted around 7:45 p.m.
Intense flames chewed through the building's roof as firefighters tackled the blaze.
All Metro Los Angeles A Line train service was shut down along Washington Boulevard between Central Avenue and Hooper Avenue until firefighters finished operations in the area.
By around 9 p.m., firefighters appeared to have gotten the upper hand on the blaze.
The church, which was built in 1903, was vacant at the time of the fire, and no injuries were reported.
It took 116 firefighters two hours, 16 minutes to extinguish the blaze at the 7,151 square-foot structure amid heavy flames and arching, fallen high-voltage power lines, LAFD said.
The church was most recently occupied by the Christian Light Missionary Baptist Church, but the building was recently listed for sale.
It was not immediately known what caused the fire. An investigation is ongoing.
City News Service contributed to this report.