Using green chem. principles in chromatog. has grown tremendously in recent years. Two green HPLC techniques for determining two antihypertensive binary mixtures, (Nebivolol hydrochloride/Valsartan mixture) and (Sacubitril/Valsartan mixture), were developed and validated. Green Anal. Chem. (GAC) principles were used, with the employed solvents and anal. run time having a significant impact on the method′s greenness. In the mobile phase, the organic modifier was "non-toxic" ethanol. The two-factor three-level response surface methodol. was used to optimize analyte separation in both mixtures in a short time span. For the first mixture, phosphate buffer (pH 3): ethanol (21:79 volume/volume) was used as the mobile phase, where the separation time was 2.5 min. On the other hand, the second mixture was separated using phosphate buffer (pH 3): ethanol (35:65 volume/volume) in 6 min. It is worth mentioning that using green solvents did not affect the resolution, which was 10.1 and 3.1 for the first and second mixtures, resp. Four well-known GAC evaluation techniques were used to assess the greenness of the proposed methods on a qual. and quant. level: The National Environmental Methods Index (NEMI), anal. eco-scale, Green Anal. Procedure Index (GAPI), and the Anal. GREEnness metric (AGREE). The proposed methods were statistically compared to other published chromatog. methods, and no significant differences in accuracy were discovered. Meanwhile, there is a major variation in the approaches′ greenness. The suggested procedures proved to be an excellent, environmentally friendly alternative to the previously mentioned approaches.