Objective: A simultaneous determination method was established for detecting 19 kinds of quinolones and sulfonamides in aquatic products simultaneously, by using QuEChERS combined with UPLC-MS/MS. Methods: Samples were extracted with 1.0% formic acid acetonitrile solution, ultrasonic for 1 min, and purified by QuEChERS multi-function needle filter. The sample purification and filtering were performed simultaneously. The Mass spectrometry was conducted by using positive (ESI+) electrospray ionization and multi-reactions monitoring (MRM) models, with external standard method. Results: The detection limit of 19 kinds of sulfonamides and quinolones is from 0.5 to 1.0 μg/kg. Compared with the national standard method, the detection sensitivity is improved. The added recoveries were from 81.0% to 113.0%, and the relative standard deviation (RSD) were from 0.2% to 11.7%. Conclusion: This method assisted ultrasonic extraction and QuEChERS, enhanced the efficiency of measuring quinolones and sulfonamides in aquatic products. It is a simple, rapid, sensitivity, accurate method, which provides an efficient technical means for daily monitoring of sulfonamides and quinolones in large quantities of aquatic product samples.