The present study investigates the optimization and advanced simulation of the flotation process of coarse particles (–425 + 106) using micro-nanobubbles (MNBs). For this purpose, flotation experiments in the presence and absence of MNBs were performed on coarse quartz particles, and the results were statistically analyzed. Methyl isobutyl carbinol (MIBC) was employed as a frother for generating MNBs through hydrodynamic cavitation. The significance of the operating variables, including impeller speed, air flow rate, together with the bubble size, and particle size on the flotation recovery was assessed using historical data (HD) design and analysis of variance (ANOVA). The correlation between the flotation parameters and process response in the presence and absence of MNBs was modeled using hybrid convolutional neural networks (CNNs) and recurrent neural networks (RNNs) as the deep learning (DL) frameworks to automatically extract features from input data using a CNN as the base layer. The ANOVA results indicated that all variables affect process responses statistically and meaningfully. Significant interactions were found between air flow rate and particle size as well as impeller speed and MNB size. It was found that a CNN-RNN model could finally be used to model the process based on the intelligent simulation results. Based on Pearson correlation coefficients (PCCs), it was evident that particle size had a strong linear relationship with recovery. However, Shapley additive explanations (SHAP) was considerably more accurate in predicting relationships than Pearson correlations, even though the model outputs agreed well.