Cook the pasta: Bring a large pot of salted water to a boil. Cook the elbow macaroni until just al dente (about 1 minute less than package directions). Drain and set aside.
Make the roux: In a large saucepan, melt 4 tablespoons butter over medium heat. Whisk in the flour and cook for 1 to 2 minutes, stirring constantly, until it forms a smooth paste.
Build the sauce: Slowly whisk in the warm milk and cream, about ½ cup at a time, to prevent lumps. Cook for 5–6 minutes, stirring often, until the sauce thickens and coats the back of a spoon.
Season and add cheese: Stir in salt, pepper, garlic powder, and mustard powder. Remove from heat and gradually add cheddar, mozzarella (or Gruyère), and Parmesan. Stir until smooth and creamy.
Combine with pasta: Add the drained pasta to the cheese sauce and mix until well coated.
Prepare topping: In a small bowl, toss panko breadcrumbs with 2 tablespoons melted butter until evenly coated.
Assemble and bake: Pour the mac and cheese into a greased 9x13-inch baking dish. Sprinkle breadcrumb topping evenly over the top. Bake at 375°F for 20–25 minutes, until bubbly and golden brown.
Serve: Let it rest for 5 minutes before serving. The sauce will set slightly, making it even creamier.