Abstract: A fully automatic online monitoring system for illegal drugs in wastewater has been developed, which integrates sampling, pretreatment, and instrument analysis. The method (online solid phase extraction-ultra-high performance liquid chromatography-tandem mass spectrometry) in the system could achieve simultaneous determination of 18 drugs and their metabolites in wastewater. Automatic collection, settling and twice filtering were conducted on the sample, and isotope internal standard solution was automatically added by the syringe pump. After aerating and settling for 10 min, 10 mL of sample was taken by the syringe pump, and then transported to the Waters Oasis HLB Direct Connect HP solid phase extraction column by the high-pressure infusion pump for automatic enrichment and purification with the methanol-water system. Then, the purified solution was loaded into the chromatography-mass spectrometry system by the binary ultra-high pressure infusion pump, targets in which were separated by gradient elution on the Waters ACQUITY UPLC HSS T3 chromatographic column with the mixed solution of acetonitrile and 0.1% (volume fraction) formic acid solution at different volume ratios, ionized in the positive and negative ion modes of electrospray ion source, detected by multiple reaction monitoring mode, and quantified by isotope internal standard method. It was shown that linear relationships between values of the mass concentration and peak area ratio of target to isotope internal standard were found in the ranges of 20.00-5 000.00 ng·L⁻¹ (cotinine) and 1.00-250.00 ng·L⁻¹ (the other 17 targets), respectively. The lower limits of determination were found in the range of 0.01-0.40 ng·L⁻¹. Test for recovery was made according to the standard addition method, giving recoveries in the range of 87.5%-113%, and RSDs (n=6) of the determined values were less than 10%. The proposed method was used for continuous monitoring (3 months) of drugs in wastewater of wastewater treatment plants, and the absolute relative error between determined values of drugs detected by this method and JD/Y JY02.10-2021 was not greater than 30%. Meanwhile, this method did not require manual labor, with a relatively short detection time of 60 min throughout the entire process, greatly improving the timeliness of sample analysis and providing important technical support for real-time drug monitoring for public security departments.