Over half of the world's population (4 billion people) experience severe water scarcity at least one month per year, while half a billion people experience severe water scarcity throughout the year. Despite progress from national and global interventions, a staggering proportion of the Global South remains water insecure. Rapid urban growth and associated demographic changes, climate change, and governance failure have also fostered the growth and expansion of urban informal settlements and slums where widespread poverty and environmental hazards exacerbate the impact of water insecurity on health. This article reflects on the interactions between water insecurity and urban poverty in the Global South across four categories of health outcomes: gastrointestinal diseases, mosquito-borne diseases, injuries, and mental illness. These examples highlight the mechanisms through which urban poverty exacerbates the adverse health effects of water insecurity.