Quantitative structure−activity relationship (QSAR) analysis, an in silico methodology, offers enhanced efficiency and cost effectiveness in investigating anti-inflammatory activity. In this study, a comprehensive comparative analysis employing four machine learning algorithms (random forest (RF), gradient boosting regression (GBR), support vector regression (SVR), and artificial neural networks (ANNs)) was conducted to elucidate the activities of naturally derived compounds from durian extraction. The analysis was grounded in the exploration of structural attributes encompassing steric and electrostatic properties. Notably, the nonlinear SVR model, utilizing five key features, exhibited superior performance compared to the other models. It demonstrated exceptional predictive accuracy for both the training and external test datasets, yielding R 2 values of 0.907 and 0.812, respectively; in addition, their RMSE resulted in 0.123 and 0.097, respectively. The study outcomes underscore the significance of specific structural factors (denoted as shadow ratio, dipole z, methyl, ellipsoidal volume, and methoxy) in determining anti-inflammatory efficacy. Thus, the findings highlight the potential of molecular simulations and machine learning as alternative avenues for the rational design of novel anti-inflammatory agents.