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Lipase has high economical value and an attribute that treasures wide range applications. Some of agro-industrial residues used for lipase production include coconut pulp waste, banana peels and pineapple peels. The aim of this study is to optimize the effect of inducers on the production of lipase from a tri-substrate feedstock using Aspergillus niger. Mixture and Response Surface designs were respectively used to study the effect of tri-substrate mixture and inducers (Castor oil, Jatropha oil and Olive oil) on the production of lipase using Aspergillus niger. Optimization was carried out using Response Surface Methodology (RSM) and Artificial Neural Network (ANN). The crude enzyme was extracted and Lipase activity was determined using the gravimetric method. The optimum composition of the tri-substrate feedstock obtained from the mixture design was 7.5g of coconut pulp waste, 0g of Banana peels and 7.5g of Pineapple peels. The maximum lipase yield was gotten to be 338.398 U/ml. A quadratic model was obtained to predict the concentration of lipase as a function of the inducers from RSM, while for ANN, Incremental Back Propagation (IBP) with Hyperbolic-tangent function (Tanh) for both hidden and output layers was the best model for predicting lipase production. The performance of both models was evaluated based on their R2 and Root Mean Square Error (RMSE). ANN with R2 and RMSE of 0.98677 and 11.18 respectively was superior to RSM with R2 and RMSE of 0.9702 and 16.2968 respectively. Optimization studies produced maximum lipase concentration of 456.334 U/ml and 456.85692 U/ml for RSM and ANN respectively. ANN was also considered to be more efficient because of its optimum level of inducers. The inducers were able to enhance lipase production. At maximum lipase concentration of 456.85692 U/ml, optimum levels of factors were Castor oil of 1.99980% w/w, Jatropha oil of 0.00025% w/w and Olive oil of 1.99989% w/w. It was therefore concluded that ANN is better than RSM in the modeling and optimization of the effects of inducers on lipase production.