Sandwich panels have excellent explosion and impact resistance capabilities. Thus, by combining square and circular honeycombs in various ways, innovative blast-proof steel sandwich panels were developed in this numerical study. A series of dynamic explicit analyses were performed at 1 to 3 kg of TNT blasts for a constant stand-off distance (SoD) of 100 mm to identify an efficiently designed sandwich panel. Further work was carried out to achieve successive improvements in the efficiently designed steel sandwich panel’s blast mitigation performance by applying different patterns of Al foam filling and fiber metal laminate (FML) facing. The ability to absorb energy, core crushing, and face deflection under blast loadings were utilized to examine the novel designed sandwich panels’ blast resistance. The Johnson-Cook (J-C) model and Hashin’s and Puck-Schurmann’s criteria were applied to accurately determine the damage behavior of steel and composite parts of the structures, respectively. The obtained results showed that the combination of square and circular honeycomb cores in a sandwich construction significantly increased blast resistance for both layered and unlayered honeycomb cases compared to the standard square honeycomb core employed in the sandwich structure (S-SS). A further enhancement in blast resistance was seen when the bottom honeycomb core of layered honeycomb was filled with foam. The further employment of the FML top face highly advanced the blast performance of the novel designed sandwich panel, and it can be applied to various parts of armor vehicles to save soldiers’ lives from air-blasts.