This study addresses the aerodynamic performance degradation in UAV propellers due to airframe interference by proposing an integrated design approach combining theoretical analysis, intelligent optimization, and numerical verification. Utilizing blade element theory, a rapid propeller design model is developed, and the NSGA-II multi-objective optimization algorithm is applied to optimize blade chord length and twist angle distribution. Numerical simulations highlight the asymmetric interference in the propeller flow field when installed, with the root region most affected by the fuselage. Optimization results indicate an improved propeller efficiency of 84.7% at a 300 m cruise condition, a 2.5% increase over the initial design. The thrust and power characteristics satisfy design requirements across flight stages. High-accuracy CFD simulations using RANS equations and the SST k-ω turbulence model align closely with wind tunnel tests, with a maximum error under 2%, confirming the method’s reliability. This approach offers a systematic solution for propeller design in complex interference environments and is applicable to advanced aircraft propulsion systems like solar drones and tilt-rotor aircraft.