A quantitative structure–retention relationship (QSRR) model with chemical reaction optimization algorithm (CROA) for predicting retention indices (RI) of 169 constituents of essential oils is proposed. The proposed model was internal and external validated based on , , , , Y-randomization test, , , and the applicability domain (AD). The validation results indicate that the model is robust and not due to chance correlation. In addition, the results indicate that the descriptors selection and prediction performance of the proposed model for training dataset outperforms the other two used modeling methods. The proposed model shows the highest , , and , and the lowest . For the test dataset, proposed model shows higher external validation value ( = 0.936), and lower value of compared with the other methods, indicating its higher predictive ability. In conclusion, the results reveal that the proposed model is an efficient approach for modeling high dimensional QSRRs and useful for the estimation of RI of essential oils that have not been experimentally tested.