<p>A sensitive, accurate, robust, and precise analytical quality by design (AQbD)-based RP-HPLC (reverse-phase high-performance liquid chromatography) method has been developed for the simultaneous estimation of perindopril erbumine and moxonidine hydrochloride, both used in hypertension treatment. Initially, a three-level factorial design screened various parameters impacting chromatographic responses, followed by Central Composite Design (CCD) for optimizing the critical parameters. This cost-effective isocratic method employed a Shimpack ODS C-₁₈ column (250 mm × 4.6 mm, 5 μm) as the stationary phase. The method, developed and validated in line with ICH Q2 (R1) guidelines, utilized a mobile phase comprising methanol: acetonitrile: phosphate buffer (34:30:36 v/v/v) adjusted to pH 3.5 with 1% ortho phosphoric acid, at a flow rate of 1.0 mL/min, a column temperature of 40 ºC, and UV detection at 214 nm, achieving efficient separation of both drugs. Linearity ranges were 25–125 μg/mL for perindopril erbumine (r² = 0.9996) and 1–5 μg/mL for moxonidine hydrochloride (r² = 0.9993). This newly developed RP-HPLC method effectively enables routine quantitative and simultaneous qualitative analysis of these compounds in bulk and synthetic mixtures. Additionally, the method’s greenness and environmental safety were evaluated using eco-analytical metrics (eco analytical scale, NEMI, GAPI, and AGREE), confirming its ecological capability.</p>