This paper presents a study on the explosion protection of prestressed concrete box girder, which is a commonly used in concrete bridges. The explosion protection tests of four prestressed box beams were designed with 1:5 scale. In order to evaluate the explosion performance of different protective layers, steel plate, ultra‐high‐performance concrete (UHPC) layer, and composite protective layer were used to protect the box girder. The experimental results revealed that under the effect of deck explosion, local penetrating failure occurred in the top plate of the box girder, which exhibited characteristics of punching failure. The web and bottom plate of the box girder as a whole exhibited bending characteristic. Compared with the unprotected box girder, the damage of the top plate of the protected box girder was less severe, whereas the damage of the bottom plate was greater. In working conditions 2–4, the UHPC protective box girder suffered less damage to the top plate, whereas the other protective box girders suffered more. The explosion dynamic responses of the box girder were compared, and the influences of different protective layers on the explosion dynamic response of box girder were studied. Based on the box girder damage, the protective efficiency of each protective layer under near‐explosion was studied. Based on the explosion tests, three‐dimensional numerical analysis model of box girder explosion was established. The accuracy of the numerical simulations of the box girder explosion were verified by comparing with the experimental failure data. Through the numerical results, the explosive energy dissipation capacity of different protective materials was compared and analyzed. Finally, based on the dynamic response of the box girder under different working conditions, the sensitivity of the protective layer to the dynamic responses of the box girder were studied. The analysis showed that the UHPC layer was sensitive to the change of prestress and explosion damage area of the box girder but had little influence on the rebars stress and the overall response of the box girder.