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Influenza and coronavirus disease 2019 (COVID-19) represent two respiratory diseases that have significantly impacted global health, resulting in substantial disease burden and mortality. An optimal solution would be a combined vaccine capable of addressing both diseases, thereby obviating the need for multiple vaccinations. Previously, we conceived a chimeric protein subunit vaccine targeting both influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), utilizing the receptor binding domain of spike protein (S-RBD) and the stalk region of hemagglutinin protein (HA-stalk) components. By integrating the S-RBD from the SARS-CoV-2 Delta variant with the headless hemagglutinin (HA) from H1N1 influenza virus, we constructed stable trimeric structures that remain accessible to neutralizing antibodies. This vaccine has demonstrated its potential by conferring protection against a spectrum of strains in mouse models. In this study, we designed an mRNA vaccine candidate encoding the chimeric antigen. The resultant humoral and cellular immune responses were meticulously evaluated in mouse models. Furthermore, the protective efficacy of the vaccine was rigorously examined through challenges with either homologous or heterologous influenza viruses or SARS-CoV-2 strains. Our findings reveal that the mRNA vaccine exhibited robust immunogenicity, engendering high and sustained levels of neutralizing antibodies accompanied by robust and persistent cellular immunity. Notably, this vaccine effectively afforded complete protection to mice against H1N1 or heterosubtypic H5N8 subtypes, as well as the SARS-CoV-2 Delta and Omicron BA.2 variants. Additionally, our mRNA vaccine design can be easily adapted from Delta RBD to Omicron RBD antigens, providing protection against emerging variants. The development of two-in-one vaccine targeting both influenza and COVID-19, incorporating the mRNA platform, may provide a versatile approach to combating future pandemics. Author summary: Developing a combined vaccine that can protect against both influenza and COVID-19 would be highly advantageous, considering the significant disease burden caused by these respiratory viruses. In our study, we designed an mRNA vaccine candidate that incorporates a chimeric antigen composed of components from the SARS-CoV-2 Delta variant and H1N1 influenza virus. This vaccine demonstrated strong immunogenicity, inducing robust and sustained levels of neutralizing antibodies and cellular immunity in mouse models. Importantly, it offered complete protection against homologous and heterologous influenza virus strains, as well as the Delta variant and Omicron BA.2 variant of SARS-CoV-2. This research highlights the potential and versatility of an mRNA-based two-in-one vaccine approach, providing a valuable strategy against future infection caused by influenza virus and SARS-CoV-2. [ABSTRACT FROM AUTHOR]