The antimalarial and antioxidant activities of methanolic extract of Nigella sativa seeds (MENS) were investigated against established malaria infection in vivo using Swiss albino mice. The antimalarial activity of the extract against Plasmodium yoelli nigeriensis (P. yoelli) was assessed using the Rane test procedure. Chloroquine (CQ)-treated group served as positive control. The extract, at a dose of 1.25 g/kg body weight significantly (p<0.05) suppressed P. yoelli infection in the mice by 94%, while CQ, the reference drug, produced 86% suppression when compared to the untreated group after the fifth day of treatment. P. yoelli infection caused a significant (p<0.05) increase in the levels of red cell and hepatic malondialdehyde (MDA), an index of lipid peroxidation (LPO) in the mice. Serum and hepatic LPO levels were increased by 71% and 113%, respectively, in the untreated infected mice. Furthermore, P. yoelli infection caused a significant (p<0.05) decrease in the activities of superoxide dismutase, catalase, glutathione-S-transferase and the level of reduced glutathione in tissues of the mice. Treatment with MENS significantly (p<0.05) attenuated the serum and hepatic MDA levels in P. yoelli-infected mice. In addition, MENS restored the activities of red cell antioxidant enzymes in the infected mice to near normal. Moreover, MENS was found to be more effective than CQ in parasite clearance and, in the restoration of altered biochemical indices by P. yoelli infection. These results suggest that N. sativa seeds have strong antioxidant property and, may be a good phytotherapeutic agent against Plasmodium infection in malaria.