The highly conserved extracellular domain of M2 protein (M2e) of influenza A viruses has limited immunogenicity on its own. Hence, aiming to enhance immunogenicity of M2e protein, optimal approaches remain to be established. In this study, we created recombinant fusion protein vaccines by linking M2e consensus sequence of influenza A viruses with C-terminal domain of human serum albumin (HSA). Then HSA/M2e recombinant fusion protein was studied. Our results showed that HSA/M2e could induce strong anti-M2e specific humoral immune responses in the established mice model. Administration of HSA/M2e with Freund's adjuvant resulted in a higher number of IFN-γ-producing cells compared to HSA/M2e or M2e peptide emulsified in Freund's adjuvant. Furthermore, HSA/M2e was able to reduce viral load in the mice lungs and provide significant protection against lethal challenge with an H1N1 or an H3N2 virus compared to controls. In conclusion, this study has demonstrated a potential vaccine that could provide protection in preventing the threat of influenza outbreak because of rapid variation of the influenza virus.