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As influenza A viruses remain a major threat to human health worldwide, the discovery of broadly neutralizing monoclonal antibodies that recognize conserved epitopes would facilitate the development of antibody-based therapeutic strategies. In this study, we show that a novel VH4-4-encoded human mAb named 3E1 could neutralize H1 and H5 subtype viruses in vitro and protect mice against the H1N1 and H5N6 viruses by inhibiting the low pH-induced conformational rearrangement of hemagglutinin (HA), hence blocking membrane fusion. The crystal structures of 3E1 Fab in complex with HA of two H1N1 strains reveal that 3E1, with both heavy and light chains, binds to a novel epitope of the conserved HA stem region, comprising parts of the fusion peptide, the F subdomain and the outermost β-strand preceding helix A. Together, these data suggest the potential of 3E1 as a therapeutic drug and new strategies for the development of antiviral drugs and universal vaccines against H1 and H5 subtype viruses.