In this study, the simultaneous determination of Lisinopril (LIS) and Hydrochlorothiazide(HCT) in drug samples by chemometric approaches using UV spectrophotometry has been reported as a simple alternative to using separate models for each component. Spectra of LIS and HCT were recorded at several concentrations within their ranges and were used to compute the calibration mixture between wavelengths 200 and 350 nm at an interval of 5 nm was used for data acquisition. Principal component regression was used for chemometric analysis of data and the parameters of the chemometric procedures were optimized. The analytical performances of this chemometric method was characterized by predicted residual error sum of squares (PRESS), standard error of prediction (SEP) and recoveries (%) and were compared with each other. A series of synthetic solution containing different concentrations of LIS and HCT were used to check the prediction ability of the principal component regression. This method was successfully applied to real samples, with no interference from excipients as indicated by recovery study results. The outcomes acquired in this examination firmly urge us to apply these strategies for a standard investigation and quality control of the two medications.