Safe water is crucial for human health and sustainable development, yet unsafe water disproportionately affects vulnerable populations such as women, infants, and children. Targeting the Global South, where most of the world's population resides, this study combines a systematic literature review and a health risk assessment to examine the gendered health consequences of unsafe water. A systematic review of 73 peer-reviewed articles from 2015–2022, onset to midway the UN Sustainable Development Goals (SDG) era, highlighted Nitrate (40%), fluoride (33%), and arsenic (16%) as the most reported water contaminants in the Global South. Fluoride and arsenic were selected for detailed health risk analysis based on the reporting frequency and global data availability. The results show that infants, children, and pregnant women face higher health risks from water contaminants. Women are more susceptible to endocrine-disrupting chemicals and enteric pathogens, while men have slightly higher non-carcinogenic health hazard quotients from fluoride and arsenic exposure. Despite low fluoride HQs in most countries, several nations in South America and Asia showed high arsenic HQs, indicating elevated risks of arsenicosis, cancers, and neurological disorders. The study underscores the need to address the gendered impacts of water quality decline, recognizing that water-related issues are not gender-neutral. Holistic policies incorporating gender-sensitive water quality monitoring, tailored public health initiatives, WASH infrastructure development, and inclusive community engagement are crucial for equitable access to safe water. Such aspects contribute to achieving the UN Sustainable Development Goals (SDGs) related to health, gender equality, and reducing inequalities.