Reactive oxygen species are known to mediate various pathological conditions associated with malaria. In this study, the antioxidant potential of Clerodendrum violaceum leaf extracts, an indigenous antimalarial remedy, was evaluated. Total phenol, flavonoid, selenium, vitamins C and E contents of Clerodendrum violaceum leaf extracts were determined. The free radical scavenging activities of the extracts against DPPH, superoxide anion and hydrogen peroxide coupled with their reducing power were also evaluated in vitro. Moreover, responses of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) in a rodent malaria model to a 4-day administration of Clerodendrum violaceum leaf extracts were also evaluated. The methanolic extract was found to contain the highest amounts of antioxidant compounds/element and also demonstrated the highest free radical scavenging activity in vitro. The results showed a significant decrease (p < 0.05) in SOD and CAT activities with a concurrent significant (p < 0.05) increase in GPx and GR activities in both erythrocytes and liver of untreated Plasmodium berghei NK65-infected animals compared to the uninfected animals. The extracts were able to significantly increase (p < 0.05) SOD and CAT activities and significantly reduce (p < 0.05) GPx and GR activities in both the liver and erythrocytes compared to those observed in the untreated infected animals. The results suggest the augmentation of the antioxidant system as one of the possible mechanisms by which Clerodendrum violaceum extract ameliorates secondary effects of malaria infection, alongside its antiplasmodial effect in subjects.