This study focuses on enhancing the blast resistance of composite panels through the design of heterogeneous, stiffness-varying structures optimized for energy absorption. By recognizing the varied failure modes across different regions of composite panels, the research targets the optimization of carbon, Kevlar, and glass fiber volume fractions at specific locations towards improving the performance. Using a design of experiments (DOE) approach, the effects of fiber types and volume distributions on structural failure were evaluated, supported by a 3D finite element model to predict damage evolution, material degradation, and damaged regions. Regression and optimization techniques were employed to maximize energy absorption. Results showed significant improvements, with the energy dissipation increasing by 12% to 21% over panels with uniform fiber distribution. Notely, Kevlar and carbon fibers outperformed glass fibers in blast resistance. Moreover, experimental impact testing of fabricated composite sandwich panels demonstrated a nearly 50% reduction in deflection due to the zoning effect, preventing the penetration in panels reinforced with carbon and Kevlar fibers. This optimized composite design method provides a promising approach for developing blast-resistant structures.