Malaria, a life-threatening disease caused by the protozoan parasite, Plasmodium falciparum, continues to pose a significant public health challenge worldwide. Despite extensive research and control measures, the disease remains a leading cause of morbidity and mortality. The pathogenesis of malaria is complex and multifactorial, involving a delicate balance between the host’s immune response and the parasite’s survival strategies. Oxidative stress emerges as a critical factor in this intricate interplay, serving a dual role in both the host’s defense mechanisms and the parasite’s virulence. The host’s immune response generates reactive oxygen and nitrogen species (ROS and RNS), which can directly kill parasites. However, excessive oxidative stress can damage host cells, contributing to severe malaria complications. The parasite’s haemoglobin digestion releases free heme, a pro-oxidant that exacerbates oxidative stress. Parasites also produce free radicals to aid infection, while antioxidants like glutathione help regulate ROS levels. A compromised antioxidant defense system, coupled with increased oxidants, may contribute to malaria severity. Restoring oxidative balance through antioxidant supplementation could serve as an adjunct therapy to prevent severe malaria complications. This chapter delves into the role of oxidative stress in P. falciparum-mediated malaria infection, exploring its implications for disease progression, severity, and potential therapeutic interventions.