The present study reports the characterization of four degradation products from ezetemibe (EZB) through liquid chromatography-tandem mass spectrometry (LC-MS/MS) and the development of a validated and stability-indicating reversedphase ultra-performance liquid chromatographic method for the determination of EZB in the presence of its process-related impurities in bulk drugs. The forced decomposition of EZB was carried out and studied under acidic, basic, oxidative, photolytic and thermal conditions. The degradation of EZB was observed under basic and acidic conditions, and four degradation products (DPs) were formed. Successful chromatographic separation of EZB and its degradation products were successfully separated through chromatography with a Waters Acquity HSST3 C18 stationary phase (50 × 2.1 mm, 1.7 m). The analytes were detected with a PDA detector set at 230 nm. The figures of merit for this method were adequate. The assay remained linear from concentrations of 0.09 g mL −1 to 600 g mL −1 for EZB and its four DPs (r 2 = 0.99914, 0.99945, 0.99917, 0.99923 and 0.99936 for EZB, Imp-A, Imp-B, Imp-C, and Imp-D, respectively). The method precision, which was expressed as the %RSD, ranged from 0.2 to 1.0 for the four impurities. The DPs from EZB were characterized by LC-MS/MS, and the most likely degradation and fragmentation pathways for EZB and its DPs were proposed.