Malaria is a life-threatening disease that kills over half a million people each year, a number that is predicted to increase with emerging drug resistance. New classes of drugs with mechanisms of action that differ from current antimalarial drugs are urgently needed. To address this need, we designed a peptide with a stable helix-loop-helix structure – cPF4PD – that selectively enters infected red blood cells to kill malaria parasites without damaging host cells. The selective membrane-active mechanism of cPF4PD is distinct from current small molecule drugs. Through structure-activity studies, we identified key residues required to promote helical structure, stability, selective cell permeation and antimalarial activity in vitro. We also identified suitable sites for conjugation of drug and peptide cargo for delivery to intracellular targets. Peptide-drug conjugates developed from cPF4PD provide a new and exciting approach to develop dual-action drug leads that improve efficacy of antimalarial drugs while extending their useful life through preventing development of drug resistance.