A commercial vaccine to address the high global burden of disease caused by Group A Streptococcus (GAS) is an urgent and unmet need. Messenger RNA (mRNA) lipid-nanoparticle (LNP) vaccines represent a largely untapped platform for targeting bacterial pathogens that may overcome technological and economic challenges impeding conventional vaccine platforms for large-scale manufacture and global accessibility. Here, we evaluated the immunogenicity and preclinical efficacy of a Moderna mRNA-LNP vaccine formulation based on the non-M-protein based GAS vaccine candidate, Combo#5. In this study we demonstrate mRNA-LNP constructs of individual Combo#5 antigens (SCPA, SLO, TF, ADI, and SpyCEP) expressed as either soluble or transmembrane-anchored (TM) proteins elicited strong antigen-specific IgG1, IgG2a, IgG2b and IgG3 responses in BALB/c mice, indicative of a Th1/Th2-type response. A multicomponent Combo#5 mRNA-LNP formulation of all TM constructs (Combo#5-TM) conferred protection to BALB/c and humanized plasminogen (hPLG) mice against invasive intraperitoneal and subcutaneous infection, respectively. A multicomponent Combo#5 mRNA-LNP formulation of all soluble constructs (Combo#5-soluble) only provided protection in the BALB/c intraperitoneal challenge mouse model. These findings demonstrate the utility of the Moderna mRNA vaccine platform for the development of vaccines against bacterial pathogens.