Preheat the oven to 350°F (175°C).
Brown the venison: Place a 10-inch cast iron skillet over medium-high heat. Add ground venison, diced onion, salt, pepper, and garlic and onion powder. Cook 7-10 minutes until meat is browned and onion is softened. Drain any grease if needed.
Prep the potatoes: While the meat cooks, toss diced potatoes with melted butter in a large mixing bowl until evenly coated.
Combine everything: Add the browned venison mixture to the bowl with potatoes. Stir in sour cream, cream of mushroom soup, and 1 cup of shredded cheddar. Mix until well combined.
Bake: Transfer the mixture back into the skillet, spreading evenly. Bake for 45 minutes.
Add cheese topping: Remove from oven, sprinkle remaining 1 cup of cheese on top, and return to oven for 10 more minutes until cheese is melted, bubbly, and golden.
Rest and serve: Let the casserole rest 5 minutes before serving to allow flavors to meld and the casserole to set.