Preheat your oven to 375°F (190°C). Grease a 9×13-inch baking dish.
In a large bowl, combine the ground beef, breadcrumbs, egg, ketchup, Worcestershire sauce, garlic powder, onion powder, salt, and pepper. Mix until well combined.
Press the meatloaf mixture evenly into the bottom of the prepared baking dish. Bake for 20-25 minutes until partially cooked.
Make the Mac and Cheese:

While the meatloaf is baking, melt the butter in a saucepan over medium heat. Stir in the flour and cook for 1-2 minutes to make a roux.
Gradually whisk in the milk and bring to a simmer. Cook until thickened, about 3-4 minutes.
Stir in the shredded cheddar cheese, mustard powder (if using), salt, and pepper. Mix until the cheese is fully melted and the sauce is smooth.
Add the cooked macaroni to the cheese sauce and stir until well coated.
Assemble the Casserole:

Remove the meatloaf layer from the oven and carefully spread the mac and cheese mixture over the top.
Sprinkle the extra shredded cheese and breadcrumbs over the mac and cheese layer for a crispy topping.