Malaria has been a deadly enemy of mankind throughout history, affecting over 200 million people annually, along with approximately half a million deaths. Resistance to current therapies is of great concern, and there is a dire need for novel and well-tolerated antimalarials that operate by clinically unexploited mechanisms. We have previously reported that both tambjamines and prodiginines are highly potent novel antiplasmodial agents, but they required rigor optimizations to enhance the oral efficacy, safety, and physicochemical properties. Here, we launched a comprehensive structure-activity relationship study for B-ring-functionalized tambjamines and prodiginines with 54 novel analogues systematically designed and synthesized. A number of compounds exhibited remarkable antiplasmodial activities against asexual erythrocytic Plasmodium parasites, with improved safety and metabolic profiles. Notably, several prodiginines cured erythrocytic Plasmodium yoelii infections after oral 25 mg/kg × 4 days in a murine model and provided partial protection against liver stage Plasmodium berghei sporozoite-induced infection in mice.