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Dengue virus (DENV) is a prevalent mosquito-transmitted human pathogen, causing about 100 million cases of acute dengue fever and 21,000 deaths annually worldwide. Therapeutic neutralizing antibodies against dengue virus might be effective to treat severe dengue fever. Here, we showed that human monoclonal antibody (HMAb) 9C7 bound to all four intact serotypes of DENV but not to the recombinant envelope protein, suggesting HMAb 9C7 recognized a conformational epitope of the envelope protein. Taken together our results suggested that HMAb 9C7 neutralized all four serotypes of DENV in vitro and, for DENV-1, indicated activity at the pre- and post-attachment steps in the viral life cycle. HMAb 9C7 potently protected suckling mice from lethal challenge with all four serotypes of DENV. FcγRII-mediated uptake of immune complexes and antibody-dependent enhancement at low doses of the antibody were abolished by two Leu-to-Ala (9C7-LALA) mutations or deletion of nine amino acids (9C7-9del) in HMAb 9C7 Fc. Therefore, HMAb 9C7 represented a promising prophylactic and therapeutic agent against all four serotypes of DENV. • We generated and characterized a novel DENV-specific HMAb 9C7 recognized a conformational epitope of the envelope protein. • HMAb 9C7 potently neutralized all four serotypes DENV in vitro at the pre- and post-attachment steps in the viral life cycle. • HMAb 9C7 potently protected model mice from lethal challenge with all four serotypes of DENV. • FcγRII-mediated ADE were abolished by two Leu-to-Ala mutations or deletion of nine amino acids in HMAb 9C7 Fc. [ABSTRACT FROM AUTHOR]