In recent years, ephedrine psychoactive substances have attracted much attention due to their prevalence in water bodies and potential threat to aquatic ecosystems. Psychoactive substances have been considered as a new type of environmental pollutant due to their unpredictable potential risks to the behavior and nervous system of non-target organisms. A rapid, sensitive, selective, and robust method for the quantification of three ephedrine psychoactive substances in sewage is needed. An ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for the simultaneous determination of three ephedrine psychoactive substances in water. The optimal processing conditions were determined by optimizing the chromatography-mass spectrometry and solid-phase extraction (SPE) conditions (e.g., the SPE column, sample pH, washing, and elution), and the treatment conditions were determined; this was achieved via positive ion scanning in multiple reaction monitoring mode. Poly-Sery MCX was selected as the extraction column, with samples loaded at pH 3. And 4-mL solution of 2% formic acid (FA) aqueous solution was used as the eluent; the target compounds were eluted with 5 mL of 5% NH4OH in acetonitrile (ACN) solution. The best results were obtained when the residue was resolubulization in ACN after nitrogen evaporation. The developed UPLC-MS/MS showed a good linear relationship in the range of 0-50.00 μg/L, with determination coefficients (R2) greater than 0.9990. The detection limit and quantitation limit were 0.05-0.10 and 0.20-0.50 μg/L, respectively. Recovery rates of the target compounds in blank sewage at three different concentrations ranged from 92.37% to 106.31%, with relative standard deviations (RSDs) of 0.77%-4.83% (n = 7). This method has been successfully applied to the analysis of surface water and domestic sewage, and the samples were processed stably, indicating that the method is practical for the determination of ephedrine psychoactive drugs in water bodies.