This paper focuses on the design of protective structures against the combined damage effect of preceding penetration and successive charge explosion of full-scale Earth Penetrating Weapons (EPWs). Firstly, two-way high-strength steel bars (yield strength of 1100 MPa grade) mesh layer reinforced ultra-high performance concrete (denoted as 2D HSSB-UHPC) targets with 1800 mm-diameter and 700 mm-height were cast. Two shots of 105 mm-caliber projectile penetration test on 2D HSSB-UHPC targets were conducted with impact positions at the HSSB mesh center and intersection, and the successive 5 kg TNT charge explosion test was further performed on the target with the impact position at the HSSB mesh center. It was found that the impact position has no obvious effect on the penetration resistance of the 2D HSSB-UHPC target. Secondly, the refined numerical simulations with considering both the HSSB element types and HSSB-concrete bond-slip behavior were conducted and validated by the present test. Furthermore, the effects of HSSB spacing and impact position on the anti-strike resistance against full-scale EPW were numerically discussed, and the optimal design of 2D HSSBUHPC target, i.e., spacings of HSSB and mesh layer are 300 mm and 200 mm, was determined. Finally, the resistances of four typical concrete targets, i.e., plain normal strength concrete (NSC) and UHPC, optimal 2D HSSB-UHPC, as well as newly developed three-dimensional high-strength steel bars cage reinforced ultra-high performance concrete (denoted as 3D HSSB-UHPC, Zhang et al. Constr Build Mater, 2023; 372: 130820) targets, were assessed. It was found that the depth of penetration and total destruction depth of 3D HSSB-UHPC are 55.41 %, 33.83 %, and 10.2 %, as well as 49.41 %, 24.88 %, and 5.93 % higher than those of plain NSC and UHPC, and optimal 2D HSSB-UHPC, respectively. The optimal designed 2D HSSB-UHPC targets is recommended for protective structures from aspects of protective performance, construction efficiency and costs.