African swine fever virus (ASFV) is a severe threat to the global pig industry, and domestic pigs mostly develop severe clinical manifestations upon viral invasion. Currently, there is no available vaccine against ASFV. Its capsid structural protein p72 is one of the immuno-dominant proteins. In this study, we unexpectedly obtained a p72 mutant protein (p72∆377-428) which deleted the aa 377-428 within p72 and had stable and high expression in E. coli. Using SWISS-MODEL 1.0 software, the prediction showed that p72∆377-428 was quite distinct from the wild-type p72 protein in structure. p72∆377-428 induced stronger antibody production in mice on day 42 and 56 post immunization and could recognize ASFV-infected swine sera. p72∆377-428 reduced IFN-γ production in the splenocytes from p72∆377-428-immunized mice and p72∆377-428-treated swine macrophages compared to p72. p72∆377-428 also decreased the production of pro-inflammatory cytokine genes, including IL-1β, IL-6, and IL-12, compared to p72 in mice. Further, we found that p72∆377-428 reduced the induction of pro-inflammatory cytokine genes by inhibiting AKT phosphorylation and HIF1α expression. Taken together, these findings have implications for immunological function and the corresponding mechanism of ASFV p72, and our study indicates that p72∆377-428 could serve as a novel candidate for ASFV vaccines and diagnostic reagents.