Plasmodium parasites, transmitted to human blood via the bite of the Anopheles mosquito, cause malaria, an acute and severe disease that can potentially be fatal. These parasites and their mosquito vectors proliferate in warmer climates and, therefore, are more prevalent in certain regions. In 2021, fifty percent of the global population was at risk of malaria. Although this disease can affect any individual, specific demographic groups, including young children, pregnant women, neonates, and immunocompromised individuals, are more susceptible to infection and are at higher risk of mortality. Among Plasmodium species, only P. falciparum causes cerebral malaria and is behind the most severe symptoms and fatalities. The pathogenesis of Plasmodium malaria is associated with the downstream signaling pathways and Toll-like receptors (TLRs) of innate immunity. Owing to the potential role of TLRs in the pathophysiology of malaria, TLR gene polymorphisms may be subject to selection pressure in communities where the disease is endemic. This review paper summarizes the prevailing knowledge of the fundamental characteristics of TLRs and their role in malaria disease. In addition, it throws light on the potential role of the TLR signaling system in malaria pathogenesis.