A simple, rapid, sensitive, precise and accurate high performance liquid chromatography method was developed for simultaneous determination of Chlorthalidone and Cilnidipine in human plasma using Azilsartan as internal standard (ISTD). The analytes were extracted from 500 µL aliquots of human plasma sample by direct protein precipitation technique using acetonitrile. Evaluation of content of the drugs were done by employing a mixture of acetonitrile and 0.1% orthophosporic acid (OPA) buffer in the ratio of 35:65 v/v as the mobile phase with a flow rate of 1ml/mL and injection volume of 10µL. Chromatographic separation was accomplished using Inertsil C18, (150×4.6 mm; 5µm) analytical column and the effluents were monitored at 248 nm with photo diode array (PDA) detector. The total run time was 8 min with retention time of Chlorthalidone, Cilnidipine and Azilsartan 3.516 min, 3.518 min and 2.308 min respectively. Linearity was established at a concentration range of 0.05-5.00 µg/mL for Chlorthalidone and 0.025-2.5 µg/mL for Cilnidipine. The method was validated as per the US-FDA guidelines and the results were within the acceptance criteria. And proposed method was successfully applied for the simultaneous determination of Chlorthalidone and Cilnidipine in human plasma.