Background/Objectives: In this study, the analytical quality by design (AQbD) approach was used to develop an eco-friendly reversed-phase high-performance liquid chromatography (RP–HPLC) method to identify and quantify favipiravir (FAV). Methods: A risk assessment identified factors significantly impacting method performance. Three high level risk factors (X1: ratio of solvent, X2: pH of the buffer, X3: column type) were selected to study their impact on the following output responses: peak area (Y1), retention time (Y2), tailing factor (Y3) and theoretical plates count (Y4) using D-optimal experimental design. The method operable design region (MODR) and the robust set point were calculated using a Monte Carlo simulation method using the MODDE® 13 Pro software. Results: The method was developed using an Inertsil® ODS-3 C18 column (250 mm, 4.6 mm, 5 μm, and 100 Å). The mobile phase was composed of A: acetonitrile and B: disodium hydrogen phosphate anhydrous buffer (pH 3.1, 20 mM) in a 18:82 v/v ratio, and was eluted at an isocratic-flow-rate of 1 mL/min at 30 °C with DAD detection at 323 nm. The method was validated as per the USP and ICH guidelines. The system suitability test parameters were within the USP limits. The method showed excellent linearity, sensitivity and selectivity. The optimized method showed good precision, accuracy and robustness with RSD value 〈 2 %. Additionally, the developed RP-HPLC method based AQbD approach showed excellent Analytical Eco-Scale score 〉 75, and was successfully applied for quantify FAV in the laboratory- prepared tablets. Conclusions: AQbD is a useful tool to replace existing traditional methods for the optimization of a green, validated RP-HPLC method, for the routine analysis and quality control of FAV
