Background: Since ages lawsone, an orange-colored dye from leaves of Lawsonia inermis is being used by women for self-adornment and is also used in textile industries for dyeing reasons. Objective: Comparing traditional and modern extraction modes for extraction of lawsone from L. inermis leaves and simultaneous use of response surface methodology for optimizing its extraction procedure. Materials and Methods: Design-Expert software was exploited for optimization task. Quantification of lawsone in different extracts was done by high-performance liquid chromatography using aqueous acetic acid and methanol in the mobile phase. Results: Ultrasound-assisted extraction stood out to be a supreme technique among all. Moreover, of all solvents (ethylene glycol, dimethylformamide, and methanol) examined methanol stood out to be the most effective solvent for lawsone extraction. By the inverse matrix of the regression model and point prediction, optimal conditions for lawsone extraction were laid down as - extraction temperature - 50.24°C, extraction time - 15.70 min, liquor to material ratio - 24.16 mL/g, and methanol concentration - 75.15%v/v which yielded 17.129 g of lawsone. Under similar conditions (extraction temperature - 50°C, extraction time - 16 min, liquor to material ratio - 24 mL/g, and methanol concentration - 75%v/v), 16.98 g of lawsone was yielded which was close to predicted value. Conclusion: We conclude that a non-thermal method proved to a supreme technique for lawsone extraction which has an additional benefit which of avoiding thermal degradation of compound. Furthermore, by model fitting and analysis of regression coefficients, it was confirmed that all the factors studied significantly affected lawsone yield.