The study identifies a human monoclonal antibody, CR8020, which exhibits broad neutralizing activity against most group 2 influenza A viruses, including H3N2 and H7N7, which cause severe human infections. CR8020 binds to a highly conserved epitope in the HA stalk, distinct from the epitope recognized by V_H1-69 antibodies that neutralize group 1 viruses. The crystal structure of CR8020 Fab complexed with the 1968 pandemic H3 hemagglutinin (HA) reveals that this epitope is located near the viral membrane, close to the fusion peptide. CR8020 potently neutralizes a wide spectrum of H3N2 and H7 viruses in vitro and protects mice against lethal challenge with these viruses in vivo. The identification of CR8020 and its broad neutralizing activity against group 2 viruses suggests that a cocktail of two antibodies may be sufficient to neutralize most influenza A subtypes, facilitating the development of a universal flu vaccine and broad-spectrum antibody therapies.The study identifies a human monoclonal antibody, CR8020, which exhibits broad neutralizing activity against most group 2 influenza A viruses, including H3N2 and H7N7, which cause severe human infections. CR8020 binds to a highly conserved epitope in the HA stalk, distinct from the epitope recognized by V_H1-69 antibodies that neutralize group 1 viruses. The crystal structure of CR8020 Fab complexed with the 1968 pandemic H3 hemagglutinin (HA) reveals that this epitope is located near the viral membrane, close to the fusion peptide. CR8020 potently neutralizes a wide spectrum of H3N2 and H7 viruses in vitro and protects mice against lethal challenge with these viruses in vivo. The identification of CR8020 and its broad neutralizing activity against group 2 viruses suggests that a cocktail of two antibodies may be sufficient to neutralize most influenza A subtypes, facilitating the development of a universal flu vaccine and broad-spectrum antibody therapies.