Preheat the oven to 350°F. Line a rimmed baking sheet with aluminum foil and spray with nonstick cooking spray.
In a large bowl, combine the crushed Ritz crackers, diced onion, milk, beaten eggs, salt, pepper, garlic powder, onion powder, and mustard powder. Stir and let sit for 2 minutes.
Add the ground beef and gently mix with your hands until just combined. Do not overmix.
Transfer the meat mixture to the prepared baking sheet and shape into a loaf about 9 inches long and 5 inches wide.
In a small bowl, whisk together the ketchup, brown sugar, and yellow mustard. Spread half of the glaze over the top and sides of the meatloaf.
Bake for 45 minutes.
Remove from the oven and brush the remaining glaze over the top. Bake for an additional 15 to 20 minutes, or until the internal temperature reaches 160°F.
Let the meatloaf rest for 10 minutes before slicing and serving.