Auxetic structures possess a negative Poisson ratio (ν < 0) as a result of their geometrical configuration, which exhibits enhanced indentation resistance, fracture toughness, and impact resistance, as well as exceptional mechanical response advantages for applications in defense, biomedical, automotive, aerospace, sports, consumer goods, and personal protective equipment sectors. With the advent of additive manufacturing, it has become possible to produce complex shapes with auxetic properties, which could not have been possible with traditional manufacturing. Three-dimensional printing enables easy and precise control of the geometry and material composition of the creation of desirable shapes, providing the opportunity to explore different geometric aspects of auxetic structures with a variety of different materials. This study investigated the geometrical and material combinations that can be jointly tailored to optimize the auxetic effects of 2D and 3D complex structures by integrating design, modelling approaches, 3D printing, and mechanical testing. The simulation-driven design methodology allowed for the identification and creation of optimum auxetic prototype samples manufactured by 3D printing with different polymer materials. Compression tests were performed to characterize the auxetic behavior of the different system configurations. The experimental investigation demonstrated a Poisson’s ration reaching a value of ν = −0.6 for certain shape and material combinations, thus providing support for preliminary finite element studies on unit cells. Finally, based on the experimental tests, 3D finite element models with elastic material formulations were generated to replicate the mechanical performance of the auxetic structures by means of simulations. The findings showed a coherent deformation behavior with experimental measurements and image analysis.