Background: The growing need for sustainable analytical methods in pharmaceutical analysis drives the development of greener approaches. For antihypertensive drugs like telmisartan and bisoprolol fumarate, optimizing chromatographic methods through Quality by Design and green analytical chemistry principles can enhance efficiency and reduce environmental impact. Objective: To optimize and validate a chromatographic method for the analysis of telmisartan and bisoprolol fumarate employing a Quality by Design approach, with an emphasis on green analytical chemistry. Methods: A central composite design was used to optimize three parameters: injection volume, flow rate, and acetonitrile volume in the mobile phase. The method utilized a Hypersil ODS C18 column with an acetonitrile-water mobile phase (70:30 v/v) and employed ultraviolet detection at 225 nm. The method was validated following International Conference on Harmonization guidelines, including assessments of precision, accuracy, and robustness. Environmental impacts were evaluated using the Green Analytics Procedure Index, Analytical Greenness Calculator and Blue Applicability Grade Index. Results: Response surface plots indicated the effects of injection volume, flow rate, and acetonitrile volume on retention times and resolution. The method demonstrated high precision, accuracy, and robustness under stress conditions. Method showed results in GAPI, AGREE, and BAGI, reflecting a low environmental impact and alignment with green analytical chemistry principles. Conclusion: The study successfully developed and validated a reversed-phase high-performance liquid chromatography method for telmisartan and bisoprolol fumarate that is both analytically robust and environmentally friendly, adhering to principles of green analytical chemistry.