Crews responded at around 2:26 a.m. to the 100 block of East Santa Ana Boulevard near Main Street after receiving multiple reports of the fire, according to the Orange County Fire Authority.
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Upon arrival, crews encountered the structure fully engulfed. As many as 100 firefighters helped extinguish the blaze.
Officials later confirmed the church was vacant and that no injuries were immediately reported.
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OCFA said firefighters had to go into a defensive operation.
Video showed plumes of smoke billowing over the area.
The bulk of the fire was out by about 4:30 a.m. but crews were expected to stay at the scene through the morning.
It was not known what caused the blaze.