A novel impurity profiling technique for Amlodipine Besylate (ADB) and Olmesartan Medoxomil (OSM) in fixed dose combined tablets has been proposed by HPLC with Acquity Quadrupole Dalton analyser (QDa) mass detector coupled to photodiode array (PDA) detector. This online coupling technique has significant advantage over conventional HPLC techniques that mass and spectral characteristics can be evaluated simultaneously in a single run. The chromatographic separation was achieved on ACE C18 (250 x 4.6mm id, 5µ particle size) column with gradient mode using mobile phase composition of ammonium formate buffer, methanol and acetonitrile. Finalized flow rate was 1.0 mL/min with quantification of 237 nm. Moreover, identification of potential degradation product in stability condition samples was carried out by online coupling of PDA/QDa mass detection. This QDa mass spectrum reveals protonated molecular ion peak [M+H]+ at m/z 875.5 for degradation product. This major degradation product was further characterized using MS/MS2 integrated analytical tools. The method was validated systematically in terms of specificity, precision, linearity, accuracy, limit of detection (LOD), limit of quantification (LOQ) and robustness as per International conference on harmonization (ICH) general guidelines. This proposed study can provide a creative idea and effective method for routine analysis of ADB/OSM in tablet formulation in quality control department where impurity profiling as well as identification of unknown impurities can be evaluated simultaneously.