Multi-objective optimization using the desirability function is a useful tool, which allows you to select the better conditions to maximize multiple objectives/responses simultaneously. Enzymatic hydrolysis of lignocellulosic residues requires synergistic action of three cellulase enzymes: exoglucanases (FPase), endoglucanases (CMCase) and β-glucosidase (BGL), to the complete conversion of lignocellulosic residue to fermentable sugars. In this work the production of cellulases (FPase, CMCase and BGL) in Aspergillus niger ITV-02 using delignified sugarcane bagasse (DSB), was optimized using a Box–Behnken design, where independent variables were: DSB concentration, Tween 80 concentration and pH. The multi-objective optimization method was applied to maximize the three-enzymatic activities (FPase, CMCase and BGL) simultaneously and find an optimal value between simple and multi-objective optimization. The optimal parameters were 20.69 g/L of DSB, 0.24% v/v of Tween 80 and pH 5.67, obtaining an activity FPase 0.42 U/mL, CMCase 0.35 U/mL and BGL 10.23 U/mL. The activity FPase, CMCase and BGL after optimization increased 47.62, 65 and 47.4%, respectively, with respect to the activity before optimization. Multi-objective or multi-response optimization using the desirability function (d) allowed to obtain an enzymatic extract rich in exoglucanase, endoglucanase and β-glucosidase activity by A. niger ITV-02 using DSB, in order to improve the enzymatic hydrolysis process of lignocellulosic residues and thus the production of 2G biofuels.