New strategies in vaccine development are urgently needed to combat emerging influenza viruses and to reduce the risk of pandemic disease surfacing. Being conserved, the M2e protein, is a potential candidate for universal vaccine development against influenza A viruses. Mycobacterium tuberculosis Hsp70 (mHsp70) is known to cultivate the function of immunogenic antigenpresenting cells, stimulate a strong cytotoxic T lymphocyte (CTL) response, and stop the induction of tolerance. Thus, in this study, a recombinant protein from the extracellular domain of influenza A virus matrix protein 2 (M2e), was fused to the C-terminus of Mycobacterium tuberculosis Hsp70 (Hsp70c), to generate a vaccine candidate. Humoral immune responses, IFN-γ-producing lymphocyte, and strong CTL activity were all induced to confirm the immunogenicity of M2e.Hsp70c (Hsp70359-610). And challenge tests showed protection against H1N1 and H9N2 strains in vaccinated groups. Finally these results demonstrates M2e.Hsp70c fusion protein can be a candidate for a universal influenza A vaccine.