ThispaperpresentstheresultofacombinedemploymentofAnalyticalQuality-by-DesignandGreenAnalyticalChemistryprinciplesforthedevelopmentofarobusthigh-performanceliquidchromatographymethodforsimultaneousdeterminationoffixed-dosecombinationofthreedrugs,perindopriltert-butylamine,amlodipinebesylateandindapamide.OptimumconditionswereachievedonZORBAXEclipseXDB-C18column(150mm×4.6mm,5μmparticlesize),themobilephasecomprisingacetonitrileandphosphatebuffer(30mM,pH2.7)intheratio34:66(v/v),theflowrateof1mLmin−1,injectionvolumeof10μLandUVdetectionat210nm.Byassigningthedesignspacefromtheoverlayplot,theregionswithinwhichtherobustnessofthemethodisachievedweredefinedandconfirmedbyDong’salgorithmcalculations.Theproposedmethodwasvalidatedandshowntobeapplicableforthedeterminationofthethreedrugsincommerciallyavailabletablets.Inaddition,theimpactofthemethodontheenvironmentwasassessedthroughfourdifferentanalyticaltools:NationalEnvironmentalMethodsIndex,AnalyticalEco-Scale,GreenAnalyticalProcedureIndexandAssessmentofGreenProfile.Theproposedmethodwasdeterminedtobegreener,withminimalimpactontheenvironmentwithregardtowasteproduction,energyconsumptionanduseofhazardouschemicals.