The environmental fate of non-steroidal anti-inflammatory drugs (NSAIDs) in the urban water cycle is still uncertain and their status is mainly assessed based on specific water components and information on human risk assessments. This study (a) explores the environmental fate of NSAIDs (ibuprofen, IBU; naproxen, NAP; ketoprofen, KET; diazepam, DIA; and diclofenac, DIC) in the urban water cycle, including wastewater, river, and treated water via gas chromatography-mass spectrophotometry (GCMS), (b) assesses the efficiency of reducing the targeted NSAIDs in sewage treatment plant (STP) using analysis of variance (ANOVA), and (c) evaluates the ecological risk assessment of these drugs in the urban water cycle via teratogenic index (TI) and risk quotient (RQ). The primary receptor of contaminants comes from urban areas, as a high concentration of NSAIDs is detected (ranging from 5.87 × 103 to 7.18 × 104 ng/L). The percentage of NSAIDs removal in STP ranged from 25.6% to 92.3%. The NAP and KET were still detected at trace levels in treated water, indicating the persistent presence in the water cycle. The TI values for NAP and DIA (influent and effluent) were more than 1, showing a risk of a teratogenic effect. The IBU, KET, and DIC had values of less than 1, indicating the risk of lethal embryo effects. The NAP and DIA can be classified as Human Pregnancy Category C (2.1 > TI ≥ 0.76). This work proved that these drugs exist in the current urban water cycle, which could induce adverse effects on humans and the environment (RQ in high and low-risk categories). Therefore, they should be minimized, if not eliminated, from the primary sources of the pollutant (i.e., STPs). These pollutants should be considered a priority to be monitored, given focus to, and listed in the guideline due to their persistent presence in the urban water cycle.
