A novel method for the detection of phenobarbital residue in pork using gas chromatography–mass spectrometry (GC-MS) combined with the “Quick, Easy, Cheap, Effective, Rugged and Safe” (QuEChERS) was established here. The analytes were extracted using acetonitrile, MgSO4, and NaAc solutions and purified with MgSO4+PSA+GCB+C18 adsorbents. The samples were then separated on a DB-17 capillary column (30 m × 0.25 mm × 0.25 μm) and the ion source was electron ionization (EI). The target compound was detected in the selected ion monitoring (SIM) mode; the quantitative ion was 204 m/z, the reference ion was 232 m/z, and external standard calibration was used for the quantitative analysis of phenobarbital. To optimize the pretreatment for QuEChERS, conditions such as acidification of the extraction solution, choices of extraction salts, and adsorbent type were discussed using the spike-recovery rate as the evaluation index. The derivative conditions and matrix effects were discussed as well. The results indicated that phenobarbital had satisfactory linearity from 0.05 to 0.5 μg/mL. The limit of detection (LOD) was 0.003 μg/mL and the limit of quantitation (LOQ) was 0.01 μg/mL. The recovery rates at three spiking levels (0.01, 0.05, and 0.1 μg/g) were 75.4% to 88.3%, and the relative standard deviations were 4.66% to 5.77%. The QuEChERS method combined with GC-MS was simple and convenient, which may provide a reference method for detecting hypnotic residues in meat matrix.