A single dose of oral cholera vaccine achieved 98% effectiveness in preventing cholera infections during Malawi's devastating 2022-2023 outbreak that claimed 1,700 lives from 59,000 cases. Among the 28,920 suspected cases analyzed, vaccinated individuals showed 50% lower odds of severe dehydration and significantly reduced mortality rates (1.2% versus 2.8% in unvaccinated populations). This finding challenges conventional two-dose cholera vaccination protocols and offers critical insights for rapid outbreak response in resource-limited settings. The results align with emerging evidence that single-dose strategies can provide substantial protection while maximizing vaccine distribution during emergencies. However, the study's cross-sectional design limits causal inference, and the relatively low vaccination coverage of 2% among cases suggests potential selection bias. As this remains a preprint awaiting peer review, these promising results require validation through controlled trials. The effectiveness observed here could reshape global cholera vaccination strategies, particularly for emergency response where rapid, wide distribution of single doses might save more lives than limited two-dose campaigns in outbreak scenarios.