Medicinal plants are commonly used for malaria treatment across various regions of Nigeria, and exploring these plants can lead to the discovery of new therapeutic agents. This study investigated the antiplasmodial properties of selected plants traditionally used to treat malaria in Nsukka, Enugu State, Nigeria. Leaves from three plants—Cucurbita pepo, Hibiscus rosa-sinensis, and Pennisetum purpureum—were collected, and two types of extracts were prepared from each: 70% ethanol and a 1:1 mixture of dichloromethane and methanol. The safety of the extracts was evaluated through acute toxicity tests in mice and cytotoxicity assays using human hepatoma (HUH) cells. Their antiplasmodial activity was tested in vitro against chloroquine-sensitive Plasmodium falciparum (Pf3D7) and in vivo against chloroquine-resistant P. berghei ANKA using the 4-day suppressive test in mice. Additionally, the ethanol extract of C. pepo (CpE) was assessed for hemolytic effects on human red blood cells and tested in mice with established malaria infections. Parameters measured included parasitemia after treatment, hematological indices, organ weights (brain, kidney, liver, spleen), and survival. The results showed that all extracts were non-toxic, with no cytotoxicity observed up to 100 μg/ml and no acute or delayed toxicity in mice at 2000 mg/kg. CpE demonstrated strong in vitro antiplasmodial activity with an IC50 of 3.05 μg/ml. Oral administration at 500 mg/kg resulted in significant suppression of parasitemia by approximately 51% (p < 0.01). The extract did not induce significant hemolysis in human erythrocytes at concentrations up to 1 mg/ml. In mice with established infections, a 300 mg/kg dose of CpE significantly prevented anemia by maintaining hematocrit levels (p < 0.01). The extract also significantly increased red blood cell and platelet counts (p < 0.05), and hemoglobin levels were notably elevated at doses of 100 and 300 mg/kg. Moreover, CpE dose-dependently reversed the increases in liver and spleen weights observed in untreated, infected mice. These findings suggest that C. pepo is a promising candidate for further research to identify its bioactive compounds and elucidate its potential mechanisms of antimalarial activity.
