Objective To establish a new method for simultaneous detection of quinolones (QNs) and sulfonamides (SAs) in aquatic products and livestock products.Methods In pretreatment, this work compares the effect of extraction solvents on the recoveries and investigates the reduction or elimination effect of purification methods such as liquid-liquid extraction (n-hexane), dispersive adsorption of the matrix (C₁₈ and ethylenediamine-N-propyl silylated silica), and general solid phase extraction (PRiME HLB) on the matrix effect. The sample is pretreated by acetonitrile with 1.0% formic acid, purified by EMR-Lipid, and separated by ACQUITY UPLC^?HSST₃ column (3.5 μm, 2.1 mm×100 mm) in 10 min. MS detection is performed by multi-reaction monitoring (MRM) in positive ion mode. QNs and SAs are quantified by the external standard method.Results The calibration curves of QNs and SAs exhibit a good linear relationship with the correlation coefficients (R²) exceeding 0.99, in the range of 1.0~100.0 ng/mL. The limits of detection (LODs) and quantification (LOQs) are 1.0 and 2.0 μg/kg, respectively. The average recoveries of QNs and SAs are between 61.9% and 115.3% under low, middle, and high spiked levels and the relative standard deviations (RSDs) are less than 15% (n=6).Conclusion Compared with literature and standard methods, the established method increases the scope of application and reduces the pre-treatment process and cost.