Mpox virus (MPXV) caused a global outbreak in 2022. Although smallpox vaccines were rapidly deployed to curb spread and disease among those at highest risk, breakthrough disease was noted after complete immunization. Given the threat of additional zoonotic events and the virus’s evolving ability to drive human-to-human transmission, there is an urgent need for an MPXV-specific vaccine that confers protection against evolving MPXV strains and related orthopoxviruses. Here, we demonstrate that an mRNA-lipid nanoparticle vaccine encoding a set of four highly conserved MPXV surface proteins involved in virus attachment, entry, and transmission can induce MPXV-specific immunity and heterologous protection against a lethal vaccinia virus (VACV) challenge. Compared with modified vaccinia virus Ankara (MVA), which forms the basis for the current MPXV vaccine, immunization with an mRNA-based MPXV vaccine generated superior neutralizing activity against MPXV and VACV and more efficiently inhibited spread between cells. We also observed greater Fc effector T _H 1-biased humoral immunity to the four MPXV antigens encoded by the vaccine, as well as to the four VACV homologs. Single MPXV antigen–encoding mRNA vaccines provided partial protection against VACV challenge, whereas multivalent vaccines combining mRNAs encoding two, three, or four MPXV antigens protected against disease-related weight loss and death equal or superior to MVA vaccination. These data demonstrate that an mRNA-based MPXV vaccine confers robust protection against VACV.