The H7N9 influenza virus causes high-mortality disease in humans but no effective therapeutics are available. Here we report a novel human monoclonal antibody, m826, which bound to H7 hemagglutinin (HA) with subnanomolar affinity at pH 5.0 and 10-fold lower affinity at neutral pH. The high-resolution (1.9 ?) crystal structure of m826 complexed with H7N9 HA indicated that m826 binds to a novel unique epitope which could explain its pH sensitivity. Furthermore, m826 fully protected mice against lethal challenge of H7N9 virus, indicating that m826 is highly effective in vivo likely due to its ability to induce potent ADCC. Interestingly, immunogenetic analysis indicated that m826 is a germline antibody and m826-like sequences can be identified in H7N9-infected patients, healthy adults and newborn babies. The unique m826 properties offer a template for H7N9 vaccine immunogens, a promising candidate therapeutic, and a new tool for exploring mechanisms of virus infection inhibition by antibodies.