Inflammatory diseases such as asthma, rheumatoid arthritis, and cardiovascular conditions are driven by overproduction of leukotriene B4 (LTB4), a potent inflammatory mediator. Leukotriene A4 hydrolase (LTA4H) plays a critical role in converting leukotriene A4 into LTB4, making it a prime target for drug discovery. Despite ongoing efforts, developing effective LTA4H inhibitors has been challenging due to the complex binding properties of the enzyme and the structural diversity of potential inhibitors. Traditional drug discovery methods, like high-throughput screening (HTS), are often time-consuming and inefficient, prompting the need for more advanced approaches. Quantitative Structure-Activity Relationship (QSAR) modeling, enhanced by ensemble machine learning techniques, provides a promising solution by enabling accurate prediction of compound bioactivity based on molecular descriptors. In this study, six ensemble machine learning methods—AdaBoost, Extra Trees, Gradient Boosting, LightGBM, Random Forest, and XGBoost—were employed to classify LTA4H inhibitors. The dataset, comprising 636 compounds labeled as active or inactive based on pIC50 values, was processed to extract 450 molecular descriptors after feature engineering. The results show that the LightGBM model achieved the highest classification accuracy (83.59%) and Area Under the Curve (AUC) value (0.901), outperforming other models. XGBoost and Random Forest also demonstrated strong performance, with AUC values of 0.890 and 0.895, respectively. The high sensitivity (95.24%) of the XGBoost model highlights its ability to accurately identify active compounds, though it exhibited slightly lower specificity (61.36%), indicating a higher false-positive rate. These findings suggest that ensemble machine learning models, particularly LightGBM, are highly effective in predicting bioactivity, offering valuable tools for early-stage drug discovery. The results indicate that ensemble methods significantly enhance QSAR model accuracy, making them viable for identifying promising LTA4H inhibitors, potentially accelerating the development of anti-inflammatory therapies.