In this study, we present a robust and reliable LC-MS/MS method for the quantification of amlodipine and Telmisartan in human plasma, employing amlodipine D4 and Telmisartan 13CD3 as internal standards (IS). By employing ethyl acetate extraction, we achieved efficient analyte recovery and purification. The chromatographic separation was accomplished on a C18 column (100 mm × 4.6 mm, 5 μm), with a mobile phase composed of acetonitrile and 5 mM ammonium acetate, supplemented with 0.1% formic acid, delivered at an isocratic flow rate of 0.700 ml/min. Employing positive ion pneumatically assisted electrospray, the compounds of interest and their respective IS were ionized, and the multi-reaction monitoring (MRM) mode was utilized for detection. The developed method exhibited exceptional sensitivity and reproducibility, allowing for accurate quantification of amlodipine and Telmisartan in complex human plasma matrices.