Notwithstanding the presence of a smallpox vaccine that is effective against monkeypox (mpox), developing a universal vaccine candidate against monkeypox virus (MPXV) is highly required as the mpox multi-country outbreak has increased global concern. MPXV, along with variola virus (VARV) and vaccinia virus (VACV), belongs to the Orthopoxvirus genus. Due to the genetic similarity of antigens in this study, we have designed a potentially universal mRNA vaccine based on conserved epitopes that are specific to these three viruses. In order to design a potentially universal mRNA vaccine, antigens A29, A30, A35, B6, and M1 were selected. The conserved sequences among the three viral species—MPXV, VACV, and VARV—were detected, and B and T cell epitopes containing the conserved elements were used for the design of the multi-epitope mRNA construct. Immunoinformatics analyses demonstrated the stability of the vaccine construct and optimal binding to MHC molecules. Humoral and cellular immune responses were induced by immune simulation analyses. Eventually, based on in silico analysis, the universal mRNA multi-epitope vaccine candidate designed in this study may have a potential protection against MPXV, VARV, and VACV that will contribute to the advancement of prevention strategies for unpredictable pandemics.