The aim of the present study was to evaluate the efficacy of pyrimethamine-loaded poloxamer 407 nanomicelles onPlasmodium berghei strain NICD as a model for human malaria.Initially, pyrimethamine-loaded nanomicelles were prepared and their zeta potential, particle size, and polydispersity index were measured. For antiplasmodial assessment, 54 mice were divided randomly into 6 groups, 4 of which were infected intraperitoneally with the parasite and received pyrimethamine-loaded nanomicelles (2 mg/kg), pyrimethamine (2 mg/kg), or nanomicelles (2 mg/kg). The parasitemia rate, survival rate, and histopathological changes of liver, spleen, and kidney were examined in the groups and were compared with the negative and positive control groups.The results showed that the mean parasitemia rate was statistically significant between the nanoformulated pyrimethamine group and each of the other groups (P < 0.05). Moreover, the survival rate of the mice in the nanoformulated pyrimethamine group was highly significant as compared to each of the other groups (P < 0.01) so that seven of the nine mice survived in this group. The main findings of the histopathological changes were that in the nanoformulated pyrimethamine the hepatic necrotic in the liver, lymphoid hypoplasia in the spleen, and tubular nephrosis and perivascular and interstitial lymphocytic infiltration in the kidney were considerably lower than the pyrimethamine and the positive control groups.As a whole, the pyrimethamine-loaded nanomicelles showed a potent antimalarial activity and can be considered as a candidate for further examinations on the availability of an antimalarial drug.