The Mekong River holds significant importance as a transnational water system within the Asian region. This study investigated the pollution characteristics, origins, and health risks associated with eighteen toxic metal (loid)s (TMs) across various depths in five cascade reservoirs located in the upper Mekong. The findings revealed that naturally sourced TMs (As, Cd, Li, Mo, Sb, and Sr) exhibited elevated levels in upstream reservoirs due to the interception effects of cascade dams. Anthropogenically sourced TMs (Co, Cu, Ni, Pb, and Zn) showed heightened concentrations in downstream reservoirs, linked to increased human activities in the downstream region. In deep-water reservoirs, the vertical distribution of redox-sensitive elements was influenced by thermal stratification, with concentrations of As, Cs, Li, Mo, Rb, Sr, and U notably higher in the hypolimnion than the epilimnion. Importantly, the concentrations of all elements in these cascade reservoirs meet Chinese and WHO drinking water standards. Water quality index (WQI: 9.2–19.1), heavy metal evaluation index (HEI: 0.96–1.37), and Nemerow index (NI: 0.35–0.56) confirmed the commendable quality of the cascade reservoir waters. The health risk assessment identified As, Sb, U, and Tl as primary contributors to non-carcinogenic risks in the cascade reservoirs. In the context of a series of cascade dams along this substantial river, this research establishes a solid foundation for preventing TM pollution and ensuring the long-term sustainability of water resources.