The present study proposes the hybrid machine learning algorithm of artificial neural network-genetic algorithm-response surface methodology (ANN-GA-RSM) to modelthe performance and the emissionsof a single cylinder diesel engine fueled by diesel and propylene glycol additive. The evaluations areperformed using the correlation coefficient (CC), and the root mean square error (RMSE) values. The best model for prediction of the dependent variables is reported ANN-GA with the RMSE values of 0.0398, 0.0368, 0.0529, 0.0354, 0.0509 and 0.0409 and CC 0.988, 0.987, 0.977, 0.994, 0.984, 0.990, respectively for brake specific fuel consumption (BSFC), brake thermal efficiency (BTE), CO, CO2, NOx and SO2. The proposed hybrid model reduces BSFC, NOx, and CO by −30.82%, 21.32%, and 11.32%, respectively. The model also increases the engine efficiency and CO₂ emission by 17.29% and 31.05%, respectively, compared to a single RSM in the optimized level of independent variables (69% of biodiesel's oxygen content and 32% of the oxygen content of propylene glycol).