The water quality–uranium solubility nexus represents a complex, integrated challenge requiring multidisciplinary investigation. This chapter explores the path to understanding this nexus and the related challenges, along with appropriate future directions. Uranium, a naturally occurring radioactive element, has highly variable solubility in water and is influenced by a wide range of chemical, geological, hydrological, and anthropogenic factors. Its mobility and complexity in terms of solubility are governed by its hexavalent uranyl form, which poses serious environmental and public health risks due to its presence in diverse water sources, including groundwater, surface water, and even treated effluents. The solubility of uranium is governed by multiple interdependent water quality parameters, surrounding environmental conditions, and dynamic geochemical interactions. This chapter highlights all such cases that influence uranium behavior in both natural and human-impacted settings. This work further discusses transformation mechanisms, competitive ion binding, time-dependent leaching, and the role of radioactive decay products in modifying uranium mobility in the environment. Recognizing the multifactorial complexity of uranium solubility, this chapter advocates for integrated and interdisciplinary strategies. A holistic approach is essential for ensuring long-term water security and safeguarding both ecological and human health in regions affected by uranium contamination.