Malaria continues to pose a significant global health threat, and the emergence of drug-resistant malaria exacerbates the challenge, underscoring the urgent need for new antimalarial drugs. While several machine learning algorithms have been applied to quantitative structure-activity relationship (QSAR) modeling for antimalarial compounds, there remains a need for more interpretable models that can provide insights into the underlying mechanisms of drug action, facilitating the rational design of new compounds. This study develops a QSAR model using Light Gradient Boosting Machine (LightGBM). The model is integrated with SHapley Additive exPlanations (SHAP) to enhance interpretability. The LightGBM model demonstrated superior performance in predicting antimalarial activity, with an ac-curacy of 86%, precision of 85%, sensitivity of 81%, specificity of 89%, and an F1-score of 83%. SHAP analysis identified key molecular descriptors such as maxdO and GATS2m as significant contributors to antimalarial activity. The integration of LightGBM with SHAP not only enhances the predictive ac-curacy of the QSAR model but also provides valuable insights into the importance of features, aiding in the rational design of new antimalarial drugs. This approach bridges the gap between model accuracy and interpretability, offering a robust framework for efficient and effective drug discovery against drug-resistant malaria strains.