To display antigenic protein on the surface of virus-like particles (VLPs) presents a potentially powerful strategy for vaccine development. We genetically engineered the major capsid protein VP1 of foot-and-mouth disease virus (FMDV) into the predominant epitope C of HBV core gene to yield a chimeric core-VP1 VLP. The VLP was successfully expressed in HeLa cells transfected with core-VP1 DNA construct. Compared with a regular VP1 DNA construct, immunization with core-VP1 DNA induced significantly higher levels of antigen-specific IgG production, T cell proliferation, cytotoxic T lymphocyte response, and cytokine production in mice. Most importantly, the level of neutralizing antibody elicited by core-VP1 immunization was significantly higher than that with VP1 DNA immunization, which correlated well with animal protection level from subsequent live FMDV challenge. Thus, immunization with chimeric VLP induces higher efficacy and provides an attractive DNA vaccine strategy for controlling FMDV infection in future.