Place the ground beef, breadcrumbs, egg, ¼ cup ketchup, onion, garlic powder, onion powder, salt, and pepper in a mixing bowl. Mix with clean hands until evenly combined.
Shape the mixture into a compact loaf about 2 inches thick and set it inside the slow cooker.
Cover and cook on low for 6 hours.
Stir together the remaining ¼ cup ketchup, brown sugar, and mustard in a small bowl.
Spread the glaze over the top of the meatloaf. Cover and cook for 1 more hour.
Turn off the slow cooker and let the meatloaf rest for 10 minutes before slicing.