Ni and Al powders with particle size of 5 μm and 45—75 μm (1#), 0.2 μm and 45—75 μm (2#), 0.2 μm and 0.5 μm (3#), respectively, and with molar ratio of 1:1 were mixed, and then Ni/Al energetic structural material samples were prepared by vacuum hot-pressing. The effect of powder particle size on the compression performance and energy release characteristics of the samples was studied. The results show that the three samples all had a Al3Ni diffusion layer formed at the Ni/Al interface. In 1# sample, the Ni particles uniformly distributed in the continuous Al matrix, and the compression performance was relatively good. In 2# sample, the Ni particles agglomerated, and the relative density and compressive strength were the lowest. In 3# sample, the Ni phase was continuous matrix, and the densification and compressive strength were the highest, but the most Al3Ni was formed. As the particle size of the powders decreased, the exothermic reaction energy density of the three samples increased, up to 1 147.8 J·g-1, the reaction activation energy was reduced, and the energy release efficiency was improved. The energy release characteristics of 3# sample were the best.