Malaria remains one of the most significant global health challenges, particularly in tropical and subtropical regions, with sub-Saharan Africa bearing the highest burden. Advances in malaria control, including insecticide-treated nets (ITNs), indoor residual spraying, and artemisinin-based combination therapies (ACTs), have reduced malaria cases and deaths. However, the emergence and spread of antimalarial drug resistance, especially to artemisinin, present a growing threat to malaria control and elimination efforts. Resistance to ACTs, characterized by delayed parasite clearance due to kelch13 mutations, is most prevalent in Southeast Asia and is beginning to emerge in Africa. This systematic literature review examines the global impact of drug resistance on malaria transmission, treatment efficacy, and control strategies. Findings reveal that drug resistance undermines treatment effectiveness, increases transmission potential, and imposes significant operational and economic challenges. Resistance hotspots in Southeast Asia, sub-Saharan Africa, and South Asia are expanding, driven by human migration and inadequate surveillance systems. The review highlights the need for strengthened molecular surveillance, the development of triple ACT therapies, and region-specific interventions to address resistance patterns. Without coordinated global efforts, drug resistance will continue to undermine progress toward malaria elimination, exacerbating the disease’s global burden. This review underscores the urgent need for innovative treatment strategies, improved surveillance systems, and international collaboration to contain the spread of drug-resistant malaria and ensure the sustainability of malaria control programs worldwide.