Objective To establish a screening method for illegally added oxyphenisatine and its derivatives in dietetic foods using ultra-performance liquid chromatography (UPLC) and UPLC quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS).Methods A UV spectral library was constructed using reference standards, and a high-resolution mass spectral database containing retention time, precursor ions, and characteristic fragment ions was established. Tandem mass spectrometry (MS/MS) was employed to elucidate characteristic fragmentation pathways of oxyphenisatine compounds and to determine their diagnostic fragment ions. The UPLC-Q-TOF-MS method was further evaluated for data processing, specificity, limit of detection (LOD), and robustness.Results Oxyphenisatine compounds exhibited similar spectral features, with diagnostic fragment ions at m/z 224.070 6 and m/z 196.075 7. Chlorinated derivatives produced characteristic ions at m/z 258.032 1 and m/z 230.037 2, while fluorinated derivatives yielded ions at m/z 242.061 1 and m/z 214.066 2. The LODs ranged from 0.5 to 5.0 mg/kg. In actual sample analysis, one unknown oxyphenisatine compound was detected and confirmed to be a fluorinated diacetophenbutate.Conclusion This method demonstrates strong anti-interference capacity, good stability, and is suitable for the rapid screening and confirmatory analysis of oxyphenisatine compounds in dietetic foods.