We have established a system of in vitro and in vivo assays to prioritize plant extracts that can serve as a source of drug candidates for the treatment of malaria, an infectious disease that affects nearly 40% of the world's population. In the present study, we have investigated the biological potential of one such plant-derived drug lead, cepharanthine. In vitro growth inhibition studies indicated this compound possessed good antiplasmodial activity without mediating a cytotoxic response. Based on this selectivity, evaluations were performed with an in vivo mouse model. Moderate activity was observed, inhibiting parasite growth by 46% at a dose of 100 mg/kg body weight (BW). We further assessed the ability of cepharanthine to serve as a drug in combination with a standard antimalarial regimen. Like chloroquine, cepharanthine inhibited the trophozoite stage of parasite growth. Isobolographic analyses revealed synergism with chloroquine, but only with the drug-resistant malaria clone, and single-dose drug-interaction studies demonstrated that cepharanthine lowered the half-maximal inhibitory concentration of chloroquine from 148.5 to 37.8 nM. In summary, since activity in the mouse model was only moderate, cepharanthine may be of greater value as a modulator of resistance, capable of prolonging the clinical utility of chloroquine.