The actor's large ranch was engulfed by a bush fire in San Luis Obispo, located between Los Angeles and San Francisco.
Galecki's representative told Variety the actor was not at the property at the time of the 1,200-acre fire.
The spokesman added Galecki had not yet seen the damage, but would visit the scene once the fire was contained.
The actor's rural holiday home was one of several properties which were destroyed following the blaze, which began on Monday night.
The California Department of Forestry and Fire Protection said on Tuesday night the fire was 60% contained.
Galecki is best known for playing Dr Leonard Hofstadter in the hit US sitom, which was recently renewed for two more seasons.
"My heart goes out to all in the area who are also experiencing loss from this vicious fire, the threat of which we live with constantly, which may seem crazy to some but we do so because living in our beautiful, rural area makes it worthwhile.
"It's never the structures that create a community - it's the people. And if the people of Santa Margarita have taught me anything it's that, once the smoke has cleared, literally and figuratively, it's a time to reach out and rebuild.
"We've done it before, and will need to do it together again, and it will make our community even closer and stronger. Endless thanks to CalFire and the Sheriff's Office. I know you guys are fighting the good fight to keep us safe. So very relieved no one has been hurt."
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The Big Bang Theory's Johnny Galecki has said he is "relieved no-one has been hurt" in a fire which burned down his house.