Greening analytical methods has become of great interest in the field of pharmaceutical analysis to protect both the operators’ health and the environment. In this work, an innovative methodology combining Quality-by-Design (QbD) and Green Chemistry principles was followed to develop a single, green and robust RP-HPLC method for the quantitative analysis of impurities of both artesunate and amodiaquine drugs. Ethanol was selected as the best ecofriendly alternative solvent in substitution to the commonly used organic solvents such as acetonitrile and methanol. To achieve method objectives, resolutions between the 10 peaks were chosen as critical method attributes (CMAs) to be optimized through QbD approach. Based on a quality risk assessment, pH, temperature, and gradient slope were then selected as critical method parameters (CMPs) and a three level full factorial design was used to model the CMAs as function of the CMPs. Response surface methodology associated to Monte Carlo simulations allowed to determine the method operable domain region (MODR), i.e., the multidimensional combination of CMPs where CMAs simultaneously satisfied specifications (Rs ≥ 1.5) with a probability at least equal to 95%. Inside the MODR, the working point was chosen based on green criteria, involving a mobile phase composed of ethanol and 10 mM acetic acid only as pH modifier. The method was successfully validated for all impurities using accuracy profile methodology, which was fully compliant with the ICH Q2(R1) requirements. Finally, the method was applied to the analysis of amodiaquine and artesunate impurities in raw materials and formulations.