Ultra performance liquid chromatography tandem mass spectrum/ mass spectrum (UPLC-MS/MS) was used to detect chlorpromazine residue in porcine muscle, liver, chicken and fish. Three sample preparation methods, including QuECHERS, MCX solid-phase extraction, and direct extraction by tert-butyl methyl ether, were compared. The results showed that the limit of detection (LOD) of the three methods for chlorpromazine was 0.2 μg/kg, and the limit of quantitation (LOQ) was 0.5 μg/kg. The recovery and relative standard deviation (RSD) of the three sample preparation methods at different addition levels were 75.5%~108.1% and 2.1%~7.5%, respectively. The detection limit, recovery, and RSD meet the methodological requirements. The purifying effect of MCX solid-phase extraction was better than the other sample preparation methods. The order of recovery was as follows: MCX solid-phase extraction, QuECHERS, and direct extraction by tert-butyl methyl ether. The recoveries of all the three methods for porcine muscle were lower than that for liver, chicken and fish.