Add buttermilk and hot sauce to a large mixing bowl and stir to combine. Add the chicken, make sure it's coated with the buttermilk mixture, cover with plastic wrap or a lid, and place in the refrigerator for at least two hours prior to cooking. Think of it as a spa treatment for your chicken!
Add the oil to a large frying pan or deep fryer. Heat oil over medium or medium-high heat. It's important to use lower heat for the oil when using a thicker cut of chicken. That way you get crispy chicken that is golden and cooked through. Thinly sliced chicken cooks more quickly and can handle a little bit higher oil temperature. You want to bring the oil to a simmer, not a boil. Adjust the temperature as needed.
Mix flour and spices (paprika, garlic powder, onion powder, salt, and pepper) in a separate bowl or shallow dish. If using gluten free all-purpose flour, you'll want to increase the salt to 1 teaspoon and add another ½ teaspoon of each spice.
Dip buttermilk-coated chicken in flour mixture, making sure to coat well. Shake off excess and place piece of chicken in skillet or deep fryer. If deep frying, follow instructions for your fryer. For best results, place chicken pieces in oil two at a time so you don't overcrowd the pan. When the pan is overcrowded, the temperature of the oil will drop, leading to longer frying times, and that isn't good because the chicken will soak up too much oil and it won't be as crispy.
Fry chicken for 1 to 2 minutes per side, until golden brown and cooked through. If you don't want to cut into the chicken to make sure it has cooked through, you can use a food thermometer to check the internal temperature of the chicken. Internal temp should be 165°F.
Remove cooked chicken from hot oil and place on a wire rack to let the chicken rest and allow the excess oil to draint. If you don't have a wire cooling rack, a plate lined with paper towels works in a pinch.