For the marinade, combine buttermilk, salt, pepper, and hot sauce in a very large bowl or baking dish. Add chicken and toss to coat thoroughly. Cover and refrigerate for at least 4 hours and up to 8 hours.

Line a rimmed baking sheet with foil and place a rack on top. Combine flour, onion powder, garlic powder, pepper, salt, and cayenne in a large paper or resealable plastic bag. Working with one piece at a time, remove chicken from buttermilk allowing excess to drip off. Place chicken in bag with flour and toss to coat, pressing flour into chicken so it coats thoroughly. Transfer coated chicken to rack and let stand while preparing remaining chicken.

In a large, deep skillet, heat 1 inch of oil to 350°. Fry chicken in batches, adjusting heat as needed to maintain temperature. Cook until golden-brown, turning once, and the internal temperature of the chicken reaches 160°, 15–25 minutes. (If chicken is golden-brown but still hasn’t reached the proper internal temperature, transfer to a rimmed baking sheet and finish cooking in a hot oven.) Transfer fried chicken to paper towel-lined baking sheet to rest at least 5 minutes before serving.