A method for the determination of quinolone and sulfonamide antibiotics residues in chinese herbal powder for fishery was established by QuEChERS combined with high performance liquid chromatography-mass spectrometry (HPLC-MS/MS). The QuEChERS method was optimized in five aspects: extraction solvent selection, extraction solvent dosage, clean-up material selection and clean-up material dosage, and the method conditions with the best recovery were finally selected by using internal standard method for quantification. The results showed that the 14 antibiotics, namely, ofloxacin, enrofloxacin, lomefloxacin, difloxacin, sulfamethoxypyrimidine, sulfamethoxypyrimidine, sulfadimethoxypyrimidine, sulfamethoxypyrimidine, sulfamethoxazole, sulfamethoxazole, sulfanilamide quinoxaline, had good linearity in the range of 2~200 ng/mL, with the correlation coefficients R2 greater than 0.99 and the detection limits The average recoveries of the 14 antibiotics at three concentration levels (1 μg/kg, 25 μg/kg and50 μg/kg) were 72.5%~123.5% with the relative standard deviations of 0.9%~12.9%. The method is simple, rapid, accurate, highly sensitive and selective, and is suitable for the rapid detection of quinolone and sulfonamide drug residues in Chinese herbal powder for fishery.