The aim of this work was to apply a modeling integrated optimisation approach for a complex, highly nonlinear system for an extracellular lipase extraction process. The model was developed using mutation, crossover and selection variables of Differential Evolution (DE) based on central composite design of Response Surface Methodology. The experimentally validated model was optimized by DE, a robust evolutionary optimization tool. A maximum lipase activity of 134.13 U/gds (more than 36.28 U/gds compared to one variable at a time approach) was observed with the DE-stated optimum values of 25.01% dimethyl sulfoxide concentration, 40 mM buffer, 128.52 min soaking time and 35ºC with the DE control parameters, namely number of population, generations, crossover operator and scaling factor as 20, 50, 0.5 and 0.25, respectively. The use of DE approach improved the optimization capability and decision speed, resulting in an improved yield of 36.28 U/gds compared to the one variable at a time approach for the extracellular lipase activity under the non-optimized conditions. The developed mathematical model and optimization were generic in nature, which seemed to be useful for the scale-up studies of maximum recovery of lipase from the fermented biomass.