<p>Auxetic structures, recognized for their lightweight design, auxeticity, and exceptional mechanical properties, have garnered considerable attention from the engineering sector. The auxeticity and associated mechanical traits of these structures depend on the negative Poisson’s ratio (NPR) principle. These structures comprise a collection of repetitive unit cells, the size of which is crucial for achieving the desired performance. This study introduces a high-performing auxetic structure based on a unit cell named Mixed Star and optimizes its performance using a hybrid statistical-numerical approach. Considering the length, height, thickness, and inclination of the wall as cell parameters, a detailed test plan was generated through a statistical approach. A series of mixed-star Metamaterial (MSM) structures were modeled according to the Design of Experiment plan, and their mechanical performance, specifically energy absorption, modulus, and strength in compression and bending, was evaluated using a validated FEM model. The collected results were analyzed, revealing key effects along with their nature. In-depth analysis of the findings indicated that the auxetic behavior of the structure is closely associated with the size of its unit cell, highlighting the need for an optimized cell size to enhance structural performance. By applying an appropriate approach, the optimum cell size was determined while considering both compression and flexural loads, resulting in substantial gains in auxeticity and mechanical performance, depending on the response parameter and loading condition. This study emphasizes the potential of a hybrid statistical-numerical approach in optimizing the geometry of NPR structures to achieve superior performance, providing a valuable framework and paving the way forward for future research.</p>