Community-based reverse osmosis (RO) water treatment plants are employed as an interim solution for producing safe drinking water for the endemic areas of Chronic Kidney Disease of Unknown Etiology (CKDu) in the rural dry zone of Sri Lanka. It is recognized that RO-treated groundwater diminishes the progression of CKDu; thus, proper maintenance of these RO plants would be indispensable to protect public health. The present study broadly investigated the quality of groundwater in CKDu-endemic areas, and the performance, operations, and maintenance of the RO plants which purified this groundwater. The feedwater (i.e., groundwater) and treated water from 32 RO plants in Anuradhapura District, comprising 27 in the CKDu high-risk (HR) region and 5 in the low-risk (LR) region, were analyzed for major chemical and biological water quality parameters. Alkalinity, hardness, and microbiological parameters in groundwaters exceeded the maximum allowable levels (MALs) for drinking in all study areas. Additionally, TDS and magnesium exceeded the MALs, exclusively in the HR areas. Elevated occurrence of magnesium-predominant hardness and ionicity in groundwater showed significant relations with the incidence of CKDu. All RO plants achieved high removal rates (>95%) for excessive chemical constituents in groundwater, but the recovery rates were fairly low (~46%). The current disinfection practices in RO plants were insufficient to ensure the microbial safety of the product water. Low demand for product water, scarcity of groundwater, lack of technical capacity of the local communities, poor maintenance practices and unplanned brine removal were the key issues related to RO plant O&M. Unless properly handled, the lack of rules and regulations for RO water treatment in the CKDu-endemic region could lead to numerous environmental and public health issues in the future.