The purpose of this work is to provide a complete study of the influence of operational parameters of the supercritical carbon dioxide assisted extraction (SC CO2E) on yield of wedelolactone from Wedelia calendulacea Less., and to find an optimal combination of factors that maximize the wedelolactone yield. In order to determine the optimal combination of the four factors viz. operating pressure, temperature, modifier concentration and extraction time, a Taguchi experimental design approach was used: four variables (three levels) in L9 orthogonal array. Wedelolactone content was determined using validated HPLC methodology. Optimum extraction conditions were found to be as follows: extraction pressure, 25MPa; temperature, 40°C; modifier concentration, 10% and extraction time, 90min. Optimum extraction conditions demonstrated wedelolactone yield of 8.01±0.34mg/100g W. calendulacea Less. Pressure, temperature and time showed significant (p<0.05) effect on the wedelolactone yield. The supercritical carbon dioxide extraction showed higher selectivity than the conventional Soxhlet assisted extraction method.