The conventional reclaimed water technologies could not effectively remove the micropollutants. Although the health risks of these residual micropollutants have been evaluated by model calculation, few animal-based studies have been performed, which is essential for risk verification. Here, we used transcriptomic, metabolomic, and other biochemical techniques to reveal the toxicity variations of effluents from oxidation ditch (OD), coagulation tank (CT), biological aerated filter (BAF), and ultraviolet disinfection pool (UV) in a reclaimed water plant located in Nanjing, China. No evident toxicity reduction trend was observed along the treatment units. Compared with control and other three treatment unit effluents, long-term exposure to reclaimed water (UV effluent) aggravated oxidative stress in mice and induced abnormal lipid metabolism and immune response. Moreover, striking correlations were identified between multi-omic biomarkers (4 differentially expressed genes and 8 significant changes metabolites) and residual micropollutants (40 semi-volatile organic compounds and 6N-nitrosamines). Our results strongly highlight that the health risks of reclaimed water are mainly induced by the residual micropollutants, and more advanced treatments and stringent discharge standards are needed to ensure the safety of reclaimed water.