Capecitabine and lapatinib are two potent anti-breast cancer drugs used in combination for better therapeutic effects. The current study aims to develop a robust liquid chromatographic method to quantify capecitabine and lapatinib using the concept of analytical procedure development. Risk assessment earmarked critical method variables, and their effect on critical analytical attributes was investigated using a Box-Behnken design. The optimized chromatographic conditions use acetonitrile: 0.01M phosphate buffer of pH 3.11 (60:40, v/v) as the mobile phase. The separation was achieved on a C-18 column (250mm×4.6mm, 5µm), and the mobile phase flow was 0.9mL/min with a diode array detection at 310nm. The developed method was specific, linear (2-64µg/mL), accurate (>99%), precise (RSD100%) for quantification of the said drugs from dosage forms and biological fluids. Employing analytical eco-scale approach revealed excellent method greenness for routine quantification of capecitabine and lapatinib in vivid samples.