An innovative combination of green chemistry and quality by design (QbD) approach is presented throughthe development of an UHPLC method for the analysis of the main degradation products of dextromethor-phan hydrobromide. QbD strategy was integrated to the field of green analytical chemistry to improvemethod understanding while assuring quality and minimizing environmental impacts, and analyst expo-sure. This analytical method was thoroughly evaluated by applying risk assessment and multivariateanalysis tools. After a scouting phase aimed at selecting a suitable stationary phase and an organic solventin accordance with green chemistry principles, quality risk assessment tools were applied to determinethe critical process parameters (CPPs).