<p>Auxetic materials, known for their negative Poisson’s ratio, are increasingly explored in biomedical engineering for their exceptional mechanical properties, offering superior adaptability, durability, and potential for patient-specific designs. This study introduces a round auxetic structure based on a modified re-entrant unit cell, in which the addition of a small-diameter feature enhances the mechanical performance of the conventional re-entrant design. A combined approach of finite element simulations, response surface methodology (RSM), and experimental validation was employed to provide both predictive modeling and practical confirmation of the structure’s behavior. The strong agreement between simulation and experimental results validates the predictive accuracy of the developed models and confirms the superior auxetic behavior of the optimized designs. Increasing the small-diameter value significantly enhanced stiffness and buckling force but reduced buckling strain, indicating a trade-off between strength and deformability. In contrast, unit-cell thickness was found to be the most influential factor for stiffness and energy absorption, while also exerting a positive effect on the auxetic response. Width played a complementary role, strengthening the impact of thickness on stiffness and energy absorption. Importantly, the interaction between width and thickness emerged as the dominant factor controlling both buckling force and Poisson’s ratio.</p>