A simple reverse phase method for the selective quantification of ezetimibe (EZM), its diastereomers and other related substances was developed. The method demonstrated an excellent separation between each of the 14 impurities (including diastereomers, specified impurities and degradation products) and EZM within a runtime of 45 min. The developed method was evaluated against the reported USP method, other literature methods found that none of them was able to separate/show the absence of all the diastereomers and degradation products. The critical method parameters were optimized using central composite design. Forced degradation studies proved the method to be highly specific and the structure of all the major degradation products were confirmed by LC-MS study. The results of validation proved the method to be precise (% RSD < 4), accurate (recoveries in range of 100 ± 6%), linear (R2 > 0.999) and sensitive (LOQ ≤ 0.04% and LOD ≤ 0.01%) for all the impurities and drug. The method is suitable for both drug substance and oral solid dosage form.