A rapid and efficient multiresidue method that involves using improved QuEChERS method and liquid chromatography–electrospray tandem mass spectrometry (LC–ESI–MS/MS) was developed to measure trace levels of sulfonamides in fish tissue. This proposed method was proven to be a powerful, highly sensitive, and environmentally friendly analytical tool that requires minimal sample preparation. The typical MS/MS fragmentation patterns of the [M+H] + were 156m/z, 108m/z, and 92m/z. Separation was performed on HC-C18 columns with a gradient elution by using methanol −5mM ammonium acetate containing formic acid (pH 3.5). This method was validated and exhibited favorable performance as well as acceptable accuracy (80.2–93.5%), precision (3.82–8.71%), sensitivity (limits of detection (LODs) 0.43–1.22μgkg −1 , limits of quantification (LOQs) 1.27–3.71μgkg −1 ; decision limit (CCα) 1.49–10.9μgkg −1 , detection capability (CCβ) 1.71–11.4μgkg −1 ), and an acceptable matrix effect (−18.2–18.4%). This methodology has been successfully applied in analyzing various fish tissue from local markets.