•A multi-class multi-residue analytical method for veterinary drugs was developed.•A total of 132 veterinary drugs from almost 15 classes were investigated.•A magnetic hypercrosslinked polystyrene-based MSPE was developed.•The methodology was applied to the trace drug analysis of milk. A quantitative multi-class multi-residue analytical method was developed for the determination of veterinary drugs in milk by high-performance liquid chromatography – tandem mass spectrometry (HPLC-MS/MS). A total of 132 veterinary drugs investigated belonged to almost 15 classes including sulfonamides, β-lactams, tetracyclines, quinolones, macrolides, nitrofurans, nitroimidazoles, phenicols, lincosamides, pleuromutilins, macrocyclic lactones, quinoxaline antibiotics, benzimidazoles, anthelmintics, coccidiostats and some others. A magnetic solid-phase extraction procedure was developed using magnetic hypercrosslinked polystyrene (HCP/Fe3O4) for the sample preparation prior to HPLC-MS/MS without deproteinization step. The results indicated recoveries of 85–107% for 14 sulfonamides, 85–120% for 13 β-lactams, 89–115% for 4 tetracyclines, 82–119% for 14 quinolones, 82–115% for 8 macrolides, 97–109% for 4 nitrofurans, 84–115% for 10 nitroimidazoles, 89–114% for 3 phenicols, 86–111% for 3 lincosamides, 97–102% for 2 pleuromutilins, 72–88% for 4 macrocyclic lactones, 87–104% for 4 quinoxaline antibiotics, 76–119% for 21 benzimidazoles, 79–115% for 12 anthelmintics, 81–118% for 12 coccidiostats and 75–119 % for 5 unclassified drugs, with relative standard deviations (RSDs) of less than 20%, and the LOQs ranged from 0.05 to 1 μg kg−1. This methodology was then applied to field-collected real milk samples and trace levels of some veterinary drugs were detected.