The development of transdermal patches for diclofenac sodium, an NSAID widely used for pain and inflammation, can enhance therapeutic efficacy and patient compliance while minimizing systemic side effects. This study utilizes Box-Behnken factorial design to optimize the formulation of transdermal patches containing diclofenac sodium, focusing on the effects of different polymer types and penetration enhancers on drug release and flux. Eudragit RL 100 and Eudragit RS 100 were used as the primary polymers, and penetration enhancers such as DMSO, oleic acid, and Tween 80 were evaluated. The study aimed to identify the optimal formulation parameters that maximize drug release and flux while ensuring desirable physical properties of the patches. Experimental results indicated that the optimized formulation, DFC 2005, demonstrated significant improvements in drug release and flux compared to other formulations. The optimized patches also met the criteria for physical properties such as smoothness, thickness uniformity, and folding endurance. Stability studies confirmed the formulation's robustness under various storage conditions. This approach demonstrates the efficacy of using Box-Behnken design for the systematic optimization of transdermal patches, providing a valuable framework for developing effective and patient-friendly transdermal delivery systems.