In this study, novel approach for quantitative determination of eprosartan mesylate (EPR) and hydrochlorothiazide (HCTZ) by green UV absorbance ratio method. The choice of green solvents was based on GSK solvent selection guide, the green UV absorbance ratio method was used for quantitation of studied compounds in their pharmaceutical formulations. The aim of this work is to develop sensitive method to estimate HCTZ and EPR by using UV absorbance ratio method at 231 nm as isoabsorptive point (isosbestic point) and 271 nm as max wavelength of HCTZ, the method was validated according to ICH guidelines (Guideline, 2005).This method facilitates to any analyst in industrial field to quantify any formula containing EPR or HCTZ by precise, sensitive, reliable, accurate and fully validated method without use of hazardous toxic organic solvents. The method was simple, direct and no derivatization step was needed. The method was successfully applied to the analysis of studied drugs in their commercial pharmaceutical products.