In this study, we numerically investigate the impact perforation of sandwich panels made of 0.8 mm 2024-T3 aluminum alloy skin sheets and graded polymeric hollow sphere cores with four different gradient profiles. A suitable numerical model was conducted using the LS-DYNA code, calibrated with an inverse perforation test, instrumented with a Hopkinson bar, and validated using experimental data from the literature. Moreover, the effects of quasi-static loading, landing rates, and boundary conditions on the perforation resistance of the studied graded core sandwich panels were discussed. The simulation results showed that the piercing force–displacement response of the graded core sandwich panels is affected by the core density gradient profiles. Besides, the energy absorption capability can be effectively enhanced by modifying the arrangement of the core layers with unclumping boundary conditions in the graded core sandwich panel, which is rather too hard to achieve with clumping boundary conditions.