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Preheat oven to 350 degrees F (175 degrees C). Grease a 9x13-inch baking dish.
Bring a large pot of lightly salted water to a boil. Cook spaghetti in the boiling water, stirring occasionally, until cooked through but firm to the bite, about 12 minutes. Drain water and transfer spaghetti to the prepared baking dish.
Heat a large skillet over medium-high heat. Cook and stir beef in the hot skillet until browned and crumbly, 5 to 7 minutes; drain and discard grease.
Whisk milk and egg together in a bowl; pour over spaghetti. Add pasta sauce, diced tomatoes, garlic powder, and oregano to spaghetti and mix well.
Spread ground beef over spaghetti mixture and top with 1/2 of the pepperoni. Sprinkle Italian cheese blend over pepperoni and top with the remaining pepperoni and Parmesan cheese.
Bake in the preheated oven until cheese is browned and bubbling, about 30 minutes.