Dengue is the most common vector-borne viral disease, causing nearly 400 million infections yearly. Currently there are no approved therapies. Antibody epitopes that elicit weak humoral responses may not be accessible by conventional B cell panning methods. To demonstrate an alternative strategy to generating a therapeutic antibody, we employed a non-immunodominant, but functionally relevant, epitope in domain III of the E protein, and engineered by structure-guided methods an antibody directed to it. The resulting antibody, Ab513, exhibits high-affinity binding to, and broadly neutralizes, multiple genotypes within all four serotypes. To assess therapeutic relevance of Ab513, activity against important human clinical features of dengue was investigated. Ab513 mitigates thrombocytopenia in a humanized mouse model, resolves vascular leakage, reduces viremia to nearly undetectable levels, and protects mice in a maternal transfer model of lethal antibody-mediated enhancement. The results demonstrate that Ab513 may reduce the public health burden from dengue. Display omitted •Structure-guided affinity enhancement of a cross-reactive dengue antibody•mAb neutralizes all four serotypes with a low level of viral-enhancing activity•Antibody demonstrates in vivo ability to resolve symptoms of severe dengue infection•Crystal structure of antibody-antigen validates the predicted designs A structure-based approach allows for the development of a monoclonal antibody that targets a non-immunodominant epitope to effectively neutralize all four serotypes of the dengue virus. This antibody treats several symptoms of severe infection in animal models and may provide strategies for treatment in humans.