Pressure drop (p) and collection efficiency (η) are used to evaluate the separation performance of the cyclone separator. In this study, we conducted comparative study of cyclone models using response surface methodology (RSM), back propagation neural network (BPNN), and group method of data handling (GMDH) networks to develop optimal predictive cyclone models. Also, we conducted multi-objective optimization for maximizing model and minimizing model using genetic algorithm (GA). CFD was performed instead of experimental method to get the estimated values for modeling of p and η. The validation results of CFD showed 0.5% and 2% errors for p and η, respectively, compared with the experimental data. Second, design of experiment (DOE) analysis for 10 cyclone geometrical parameters was executed to obtain the significant geometrical parameters. Vortex finder diameter D x , inlet width a, inlet height b and cone height H co have a significant effect on η and p. However, interaction effects between the geometrical parameters have small effects. The cyclone models by RSM, BPNN and GMDH based on 25 CFD training set were developed. The predictive performance results by the cyclone models were compared by 25 CFD test set. The GMDH method achieved the best prediction for p (R 2 = 99.7, RMSE = 0.102) R 2 adjusted = 98.99, RMSE = 0.0119) than the RSM, BPNN cyclone models. Additionally, uncertainty analysis was performed to estimate the quantitative performance of cyclone models. The results show that the uncertainty width of GMDH models achieved the best prediction (η: ±0.0065, p: ±0.0188). Finally, GA was applied to optimize the GMDH models simultaneously. GA generated 70 non-dominant solutions. Reproducibility of five optimal points was validated by using CFD. The trade-off optimal point showed improvement by 24.31%, 18% and 8.79% for p d 50 and η, respectively.