A method for simultaneous determination of chlorpromazine, diazepam and metolazone residues in porcine muscle, fish, liver and kidney was developed using QuEChERS and HPLC-MS/MS technique. The samples were extracted with ethyl acetate and cleaned up with C18, N-propylethylendiamine (PSA) and NH2 sorbents after using Na2SO4 as dehydrating agent. The analytes were separated by a special C18 column, Atlantis T3, and gradiently eluted with a mixed solution of 5 mmol/L formic acid and acetonitrile at a flow rate of 0.35 mL/min. The mass spectrometric analysis that quantified using isotope internal standard, was carried out with electrospray positive ion source (ESI+) and multiple reaction monitoring mode (MRM). The linearity of the calibration curves was good in the range of 0.2-5.0 μ g/L. The recoveries at three different spiked levels (0.5, 1 and 5 μ g/kg) in four matrices were in the range of 92.5%-117.8%. The repeatability expressed as relative standard deviations (RSDs) ranged from 0.7% to 11.6% (n=6). The method, with wide matrix range of application, is highly effective and sensitive and suitable for the rapid analysis of large quantities of samples.