<br> Shigellosis is a global public health challenge that mostly affects low- and middle-income countries and causes considerable morbidity and mortality among children under 5 y of age. Multi- and extensively drug-resistant<br> Shigella sonnei</i><br> strains associated with recent outbreaks in high-income countries exacerbate the problem and have prompted the World Health Organization to include<br> Shigella</i><br> spp. among the high-risk pathogens for which novel prophylactic and therapeutic tools are urgently needed. Among the most promising and cutting-edge solutions, monoclonal antibodies are gaining considerable attention in the infectious diseases field. Here, we report the discovery of human monoclonal antibodies against<br> S. sonnei</i><br> , a species whose prevalence is constantly increasing worldwide and is associated with frequent drug-resistant infections. We isolated antibodies generated in response to an experimental<br> S. sonnei</i><br> vaccine followed by a controlled human infection and screened them by using a panel of high-throughput assays. We identified a molecule which exhibited potent bactericidal activity in vitro, inhibition of invasion of epithelial cells and conferred full protection from<br> S. sonnei</i><br> infection in vivo. Overall, our study provides a candidate antibody that can rapidly progress to industrial development for application as a prophylactic, therapeutic, and diagnostic tool against shigellosis.<br>