Foot and mouth disease (FMD) is a highly contagious viral disease of cloven-hoofed animals. Previously, we found that the epitope peptide EP141-160 displayed on virus-like particles (VLP) for use as a vaccine showed high immunoreactivity and conferred partially effective protection to animals. In this study, we first combined antisense RNA with VLP as a vaccine against the foot-and-mouth disease virus (FMDV) by using a prokaryotic co-expression system. The antisense RNA against the 3D genes of FMDV was packaged into VLP with EP141-160 presented on the surface. ELISA and Western blotting proved that the epitope-RNA VLP eliciting an immune response to FMDV in mice. Furthermore, the potency of the vaccine was tested in mice and guinea pigs. The results indicated that the epitope-RNA VLP vaccine protected 40% of suckling mice and 85% (17/20) of guinea pigs from FMDV. Based on the experimental data, the epitope-RNA VLP vaccine should have value in exploring and developing vaccines against FMDV in the future.