Preheat the oven to 425°F (220°C). Toss the butternut squash with the olive oil, 1/4 teaspoon salt, and 1/8 teaspoon black pepper. Spread in a single layer on a rimmed baking sheet.
Roast the squash for 20 to 25 minutes, turning once halfway through, until very tender and lightly browned around the edges.
Reduce the oven temperature to 375°F (190°C). Lightly grease a 9-by-13-inch baking dish.
Meanwhile, bring a large pot of salted water to a boil. Cook the elbow macaroni for approximately 2 minutes less than the package directions for al dente. Drain well and set aside.
Transfer the roasted squash to a blender. Add 1 cup of the whole milk and blend until completely smooth.
Melt 4 tablespoons unsalted butter in a large saucepan over medium heat. Whisk in the flour and cook for about 1 minute, whisking constantly.
Slowly whisk in the remaining 2 cups whole milk, followed by the blended squash mixture. Cook over medium heat for 4 to 6 minutes, whisking frequently, until the sauce thickens enough to lightly coat the back of a spoon.
Reduce the heat to low. Stir in the Dijon mustard, garlic powder, smoked paprika, 1/2 teaspoon salt, and 1/4 teaspoon black pepper.
Remove the saucepan from the heat. Gradually stir in the 3 cups sharp cheddar and 1/2 cup Parmesan until melted and smooth.
Add the drained macaroni to the cheese sauce and stir until evenly coated. Transfer to the prepared 9-by-13-inch baking dish.
Combine the panko breadcrumbs, 1/4 cup Parmesan, and 2 tablespoons melted butter. Sprinkle evenly over the macaroni.
Bake at 375°F (190°C) for 18 to 22 minutes, until the sauce is bubbling around the edges and the breadcrumb topping is golden brown.
Remove from the oven and let the mac and cheese rest for 10 minutes before serving.