In the current research study, the blast performance of sandwich panels with graded polyurethane foam core and aluminum face sheets with the same mass and different layering arrangements was studied experimentally and numerically. An explosive shock tube apparatus was employed to conduct the blast tests. The metallic sandwich panels with single-layer, double- and triple-layered cores were designed and fabricated at ambient pressure. The maximum displacements of face sheets at the center were measured in the experiments. All the sandwich panels exhibited a similar plastic deformation mode, which was characterized by a uniform global dome with the maximum transverse deflection taking place at the center of the panel. The ANSYS/Autodyn finite element code was also employed for further discussion on the structural response, fluid-structure interaction effect, deformation pattern, velocity response, and energy absorption capacity of the sandwich panels. For the validation of the numerical model, the simulation results in terms of the displacement of back and front face sheets at the center were compared with the corresponding experimental data. The results indicated that the graded foam core strategy would greatly affect the level of plastic deformation of the back face sheets. It was also concluded that in comparison with the back face sheet deflection of the P1MT30 (single-layer core) configuration, P3HMLT30 (triple-layered core with relative densities in descending order) and P2HLT30 (double-layered core) configurations gave a decrease by 16.8% and 8.3%, respectively, while P2LHT30 (double-layered core with relative densities in ascending order) and P3LMHT30 configurations gave an increase by 15.4% and 25%, respectively. Also, by consideration of total energy dissipation as a criterion of blast performance, the results showed that the energy absorption of P3HMLT30 and P2HLT30 configurations were reduced by 30.2% and 13.8%, respectively, compared to the P1MT30 panel.