In a large bowl, combine the flour, garlic powder, onion powder, paprika, salt, and black pepper. Mix well to combine.
Pour the buttermilk into a separate bowl. Dip each oyster mushroom into the buttermilk, allowing any excess to drip off.
Next, dredge the buttermilk-coated mushrooms in the flour mixture, ensuring they are well coated. Return them to the buttermilk and then coat with breadcrumbs, pressing gently to adhere.
In a large skillet, heat about 1 inch of vegetable oil over medium-high heat until it reaches 350°F.
Carefully add the breaded mushrooms to the hot oil in batches, frying for about 3-4 minutes on each side or until golden brown and crispy. Avoid overcrowding the pan.
Use a slotted spoon to remove the mushrooms and transfer them to a paper towel-lined plate to drain excess oil.
Serve hot with your favorite dipping sauce.