The resurgence of locally acquired malaria cases in the USA and the persistent global challenge of malaria transmission highlight the urgent need for research to prevent this disease. Despite significant eradication efforts, malaria remains a serious threat, particularly in regions like Africa. This study explores how integrating Gregor's Type IV theory with Geographic Information Systems (GIS) improves our understanding of disease dynamics, especially Malaria transmission patterns in Uganda. By combining data-driven algorithms, artificial intelligence, and geospatial analysis, the research aims to determine the most reliable predictors of Malaria incident rates and assess the impact of different factors on transmission. Using diverse predictive modeling techniques including Linear Regression, K-Nearest Neighbor, Neural Network, and Random Forest, the study found that; Random Forest model outperformed the others, demonstrating superior predictive accuracy with an R 2 of approximately 0.88 and a Mean Squared Error (MSE) of 0.0534, Antimalarial treatment was identified as the most influential factor, with mosquito net access associated with a significant reduction in incident rates, while higher temperatures correlated with increased rates. Our study concluded that the Random Forest model was effective in predicting malaria incident rates in Uganda and highlighted the significance of climate factors and preventive measures such as mosquito nets and antimalarial drugs. We recommended that districts with malaria hotspots lacking Indoor Residual Spraying (IRS) coverage prioritize its implementation to mitigate incident rates, while those with high malaria rates in 2020 require immediate attention. By advocating for the use of appropriate predictive models, our research emphasized the importance of evidence-based decision-making in malaria control strate-How to cite this paper: Komugabe, M.A.,