In response to the human Mpox (hMPX) epidemic that began in 2022, there is an urgent need for a monkeypox vaccine. Here, we have developed a series of mRNA-lipid nanoparticle (mRNA-LNP)-based vaccine candidates that encode a collection of four highly conserved Mpox virus (MPXV) surface proteins involved in virus attachment, entry, and transmission, namely A29L, A35R, B6R, and M1R, which are homologs to Vaccinia virus (VACV) A27, A33, B5, and L1, respectively. Despite possible differences in immunogenicity among the four antigenic mRNA-LNPs, administering these antigenic mRNA-LNPs individually (5 μg each) or an average mixture of these mRNA-LNPs at a low dose (0.5 μg each) twice elicited MPXV-specific IgG antibodies and potent VACV-specific neutralizing antibodies. Furthermore, two doses of 5 μg of A27, B5, and L1 mRNA-LNPs or a 2 μg average mixture of the four antigenic mRNA-LNPs protected mice against weight loss and death after the VACV challenge. Overall, our data suggest that these antigenic mRNA-LNP vaccine candidates are both safe and efficacious against MPXV, as well as diseases caused by other orthopoxviruses.