Prepare the Oven and Pans: Preheat the oven to 350°F (175°C). Grease two 9×5-inch loaf pans with butter or nonstick cooking spray. For easier removal, line the pans with parchment paper, leaving a little overhang on the long sides. Set the pans aside. The parchment overhang works like handles, so you can lift the loaves out cleanly after baking.
Prepare the Blueberries: Place the blueberries in a medium bowl and sprinkle them with the 2 tablespoons of reserved flour. Gently toss until the berries are lightly coated. The flour coating helps distribute the berries throughout the batter and can reduce sinking during baking. If you are using frozen berries, keep them frozen until you are ready to fold them in.
Cream the Butter, Cream Cheese, and Sugar: In a large mixing bowl, beat the softened butter, cream cheese, granulated sugar, and vanilla with an electric mixer. Keep mixing until the mixture is smooth, creamy, and well combined. Scrape down the sides of the bowl as needed. This step builds the loaf’s rich flavor and tender texture.
Add the Eggs: Add the eggs one at a time, beating well after each. Let each egg blend in before adding the next. The batter should look smooth and creamy once all the eggs are in. If the mixture looks slightly curdled, don’t worry. Adding the dry ingredients gradually should bring it together.
Combine the Dry Ingredients: In a separate bowl, whisk together the remaining 2 cups of flour, baking powder, and salt. Gradually add the dry ingredients to the butter mixture. Mix on low speed until the flour is incorporated and no dry streaks remain. Avoid overmixing, which can make the loaf dense rather than tender.
Fold in the Blueberries: Using a rubber spatula, gently fold the floured blueberries into the batter. Work carefully so you do not crush the berries or turn the batter purple. Make sure the berries are evenly distributed. The batter will be thick, which helps hold the berries in place as the loaves bake.
Fill the Pans: Divide the batter evenly between the two prepared pans. Smooth the tops with a spatula, spreading the batter into the corners. If you like, reserve a few blueberries to sprinkle over the tops for a pretty finish. Place the pans on the center rack of the preheated oven.
Bake: Bake for about 45 to 55 minutes, until the tops are lightly golden and a toothpick inserted into the center comes out clean or with a few moist crumbs. Begin checking toward the early end of the range, because oven temperatures and pan materials can affect the time. If the tops brown too quickly before the centers are done, cover the pans loosely with aluminum foil and keep baking.
Cool and Slice: Let the loaves cool in their pans for about 10 minutes. Carefully loosen the edges with a knife, then lift or turn the loaves out onto a wire rack. Let them cool completely before slicing. Cooling helps the crumb set, so you get neat slices that do not crumble. Serve plain, or with a little softened butter.