This study focuses on the design of the propeller layout for tilt-wing fixed-wing unmanned aerial vehicles (UAVs) with distributed electric propulsion (DEP). A numerical simulation method is used to analyze the effects of propeller diameter, quantity, and other parameters on aerodynamic performance under hover and cruise conditions. Meanwhile, aerodynamic mechanisms of propeller-wing interference are analyzed. Six sets of DEP layouts with different quantities and sizes of propellers are designed and studied. The results indicate that propeller quantity and size significantly affect the power loading, overall efficiency, and lift-to-drag ratio. In the hover state, a greater number of propellers increases the power loading, whereas employing a greater number of smaller propellers decreases the power loading. In the cruise state, a greater number of propellers enhances the overall efficiency of the DEP system, but reduces the lift-to-drag ratio of the aircraft. Comprehensive analysis shows that the Prop1–2 and Prop1–3 layouts exhibit superior overall performance in both hover and cruise conditions. This study provides crucial theoretical support for the design of tilt-wing vertical take-off and landing UAVs.