One of India’s most well-known waterways, the Yamuna River, has sadly come to the attention of many people owing to widespread pollution along its numerous segments. Significant metropolitan areas like Delhi, Mathura, Agra, Prayagraj, and others have a significant impact on the river’s ongoing pollution due to lead contamination. Lead is a well-known hazardous metal that when added into water bodies offers a serious threat to both human and animal life. Lead is routinely dumped into the Yamuna River from a variety of sources, underscoring its potential for long-lasting toxicity and the serious consequences for human health. Lead and other contaminants have been extensively introduced into the lakes, rivers, groundwater, and other water sources related to the Yamuna as a result of urban growth, agricultural and residential development, and rapid technological breakthroughs. This comprehensive review focuses on the poisoning of the Yamuna River, illuminating the complex interactions between lead toxicity and its harmful impacts on human populations.