The performance of sandwich structures against individual shock loading and fragment impact loading has been extensively examined, but little is known about their performance in the presence of simultaneous shock and impact loading. Based on a recently developed composite projectile to simulate combined shock and single fragment impact loading, the performance of aluminum honeycomb core sandwich panels (HCSPs) against combined loading is methodically examined. The achieved results reveal that the combined loading exhibits a synergistic effect compared to the single loading, i.e., increased damage of the sandwich panel and enhanced perforation resistance of the sandwich panel. After that, a three-dimensional finite element simulation is performed to explore the underlying mechanism of the synergistic effect. Numerical analysis indicates that the increased damage is a result of perforation-induced reduction of load-carrying capacity of sandwich panel, while the enhanced perforation resistance is the result of deflecting-induced perforation time delay of the perforation process. Finally, the parametric investigation of sandwich geometries such as asymmetric face sheets, core density, and core height is comprehensively conducted. The gained results reveal that both performance and synergistic effect due to combined loading are sensitive to these parameters.