Current influenza vaccines need to be updated annually owing to constant antigenic drift in the globular head of the viral surface hemagglutinin (HA) glycoprotein. The immunogenic subdominant stem domain of HA is highly conserved and can be recognized by antibodies capable of binding multiple HA subtypes. Therefore, the HA stem antigen is a promising target for the design of universal influenza vaccines. On the basis of an established lipid nanoparticle-encapsulated mRNA vaccine platform, we designed and developed a novel universal influenza mRNA vaccine (mHAs) encoding the HA stem antigen of the influenza A (H1N1) virus. We tested the efficacy of the mHAs vaccine using a mouse model. The vaccine induced robust humoral and specific cellular immune responses against the stem region of HA. Importantly, two doses of the mHAs vaccine fully protected mice from lethal challenges of the heterologous H1N1 and heterosubtypic H5N8 influenza viruses. Vaccinated mice had less pathological lung damage and lower viral titers than control mice. These results suggest that an mRNA vaccine using the conserved stem region of HA may provide effective protection against seasonal and other possible influenza variants.