Background: Recovery of Al and V from red mud, a hazardous residue of the Bayer process, using bioleaching is a nature-based waste management solution that simultaneously improves environment protection and metallurgical recoveries.Methods: For the first time, a novel hybrid multilayer Perceptron (MLP) network enhanced by an Imperialist Competitive Algorithm (ICA), and a response surface developed based on a factorial experiment design methodology (RSM) were employed and compared for, prediction optimization and optimization prediction of Al and V bioleaching by strains of A. Niger microorganisms isolated from pistachio shells and grape skins. The controlling variables were fungi source (A), adoption strategy (B), solid activation (C), solid percent (D), and bioleaching time. Considering the stochastic nature of ICA, a multi-criteria-ranking system based on accuracy and error indices was developed to select the best MLP. Probability value at 95% confidence interval, lack-of-fit, analysis of variance, R2, Adj. R2, and predicted R2 were the judges for the determination of the developed model's statistical significance.Significant Findings: Based on ANOVA, between A, B, C, and D, the effectiveness orders of A > D > C>AC>AD on Al, and A>AD>C>AC>D on V bioleaching were obtained. The superiority of the developed hybrid ICA-MLP model over the developed RSM model in predicting Al and V dissolution was determined by NSE, RSME, MAE, and MEDAE. Parameters optimization and consequently evaluating optimum condition repeatability through three repeating experiments resulted in maximum dissolution recoveries of RSM: 96.5% for Al and 91.2% for V, and ICA-MLP: 97.1% for Al and 90.3% for V. Considering the lower relative errors of repeating validation tests, it can be concluded that, although both models provide reasonable results, but the ICA-MLP methodology is more reliable (relative error <1.8%).