ABSTRACTClinical trials have shown that combining a modest dose of Rivaroxaban (RIV) with Aspirin (ASP) is more effective than ASP alone in reducing cardiovascular mortality, myocardial infarction, and stroke. A high‐performance liquid chromatography method developed using Quality by Design (QbD) effectively estimates ASP and RIV for routine pharmaceutical analysis. The Plackett‐Burman design assessed key factors including organic phase volume, mobile phase pH, flow rate, temperature, and injection volume using an Ishikawa fish‐bone diagram for risk assessment. These parameters were then optimized via Box‐Behnken design in 15 trials. The method meets the International Council For Harmonization standards with a mobile phase ratio of 45:55 (v/v) acetonitrile: buffer (pH 3, adjusted with orthophosphoric acid), a flow rate of 1 mL/min, a column temperature of 30°C, and an injection volume of 20 µL. A Phenomenex Luna C18 column (250 × 4.6 mm, 5 µm particle size) with detection at 251 nm ultra‐violet wavelength. The retention times of 4.54 min for ASP and 5.81 min for RIV were obtained. Validation confirmed linear ranges: 40–200 µg/mL for ASP and 2–10 µg/mL for RIV, with excellent recovery rates (ASP: 99.30%–101.9%; RIV: 98.52%–101.84%). Developed using QbD principles, the method proved specific, accurate, precise, sensitive, and robust for routine quality control of both compounds in pharmaceutical formulations.