This paper presents a structural optimization of a 3D-printed thermoplastic-core propeller blade for high-altitude unmanned aerial vehicles using a genetic algorithm. It aims to minimize the weight of the blade by creating longitudinal holes and spars and to minimize the blade tip deflection during operation at an altitude of 16 km. The objective is to check the validity of a 3D-printed material modeling approach for large-scale and more complex 3D-printed parts, such as hollow twisted blades. The approach is based on attentively selecting the printing parameters that reduce the anisotropy of the 3D-printed parts. The linear isotropic behavior of 3D-printed Polylactic Acid and Acrylonitrile Butadiene Styrene M30 tensile samples, which have been tested at ambient and low temperatures ([Formula: see text]), is utilized to numerically predict the experimental deformation and natural frequencies of 3D-printed substitute and twisted full blades with good accuracy. The validated linear isotropic model of each material is then used to evaluate the objectives and the constraints of the two-objective optimization process using one-way fluid–structure interaction. Four optimized blades have been selected from the Pareto fronts as candidates, printed, and tested in bending and vibration. The numerical and experimental results of the candidate blades in terms of deformation and natural frequencies are in good agreement, proving the validity of the present macroscale approach for large-scale hollow twisted blades.