A simple, accurate and precise spectroscopic method was developed for simultaneous estimation of Amiodarone Hydrochloride and Ranolazine in synthetic mixture using Second order derivative zero-crossing method. Amiodarone HCl showed zero crossing point at 249.20 nm while Ranolazine showed zero crossing point at 263.20 nm. The dA/dλ was measured at 263.20 nm for Amiodarone HCl and 249.20 nm for Ranolazine and calibration curves were plotted as 2dA/2dλ versus concentration, respectively The linear correlation was obtained (r2>0.9996) in the range of 1–20 μg/ml for Amiodarone HCl at 263.20 nm. The method was found to be linear (r2>0.9996) in the range of 10–200 μg/ml for Ranolazine 249.20 nm. The limit of determination was 0.235μg/ml and 0.271μg/ml for Amiodarone HCl and Ranolazine, respectively. The limit of quantification was 0.712μg/ml and 0.823μg/ml for Amiodarone HCl and Ranolazine, respectively. The accuracy of these method were evaluated by recovery studies and good recovery result were obtained greater than 99% shows Second order derivation zero crossing. The method was successfully applied for simultaneous determination of Amiodarone HCl and Ranolazine in binary mixture.