Background: Simultaneous analysis of drug combinations requires prior understanding of the individual physicochemical and spectroscopic behavior of each analyte and systematic optimization of chromatographic selectivity. Indapamide (IND), a thiazide-like diuretic, and losartan potassium (LOS), an angiotensin II receptor blocker, differ markedly in aqueous solubility, lipophilicity and UV absorption behavior. Objective: The present work profiled IND and LOS by preliminary physicochemical tests, FTIR, UV–visible spectrophotometry and RP-HPLC to establish analytical conditions suitable for simultaneous determination. Methods: Melting point and solubility were evaluated, FTIR spectra were interpreted for characteristic functional groups, and methanolic UV spectra were scanned from 200–400 nm. Chromatographic screening was performed on a C18 column (250 × 4.6 mm, 5 µm) using seven mobile-phase trials. Results: IND showed a melting point of 163–165°C and LOS 262–264°C. Characteristic FTIR bands supported identity of both analytes. UV maxima were approximately 236 nm for IND and 206 nm for LOS; an overlay supported 214 nm as the common HPLC detection wavelength. The optimized chromatographic system consisted of phosphate buffer pH 3.0:acetonitrile (40:60, v/v) at 1.0 mL/min. IND and LOS eluted at approximately 3.74 and 6.98 min, respectively, with a resolution of 11.22. Calibration responses were linear over 0.75–7.5 µg/mL for IND and 25–250 µg/mL for LOS, with R² values of 0.9997 and 0.9996. Conclusion: Complementary UV, FTIR and chromatographic profiling provided a rational basis for simultaneous analysis of IND and LOS and established a selective RP-HPLC condition for their quantitative determination.