Antimalarial drug resistance posed a significant challenge to malaria control in Uganda, where Plasmodium falciparum remains the predominant strain. This review examined the current status of antimalarial drug resistance in Uganda, focusing on the mechanisms underlying resistance, epidemiological trends, and the impact on malaria control programs. Chloroquine and sulfadoxine-pyrimethamine resistance have been well-documented, and recent concerns about reduced efficacy of artemisinin-based combination therapies (ACTs) highlight ongoing challenges. The review identified key mechanisms of resistance, including genetic mutations, drug efflux, metabolic pathway alterations, and potential biofilm formation. The implications of resistance on treatment efficacy, healthcare costs, and policy adjustments are discussed. Future directions included strengthening surveillance systems, optimizing combination therapies, investing in research and development, implementing integrated vector management strategies, and enhancing public education and community engagement. Related published literatures were reviewed and analysis of recent data on drug resistance patterns in Uganda was carried out and utilised in compiling this paper. By exploring these dimensions, the review aims to provide actionable insights for policymakers, healthcare providers, and researchers to effectively address drug resistance and advance malaria control efforts in Uganda. Keywords: Antimalarial Drug Resistance, Plasmodium falciparum, Chloroquine Resistance, Artemisinin-Based Combination Therapies (ACTs), Surveillance and Monitoring.