Seasonal Malaria Chemoprevention (SMC) is a WHO-approved protocol for protecting at-risk people from disease during the malaria season. Most antimalarials used in SMC, and treatment of disease, target blood stage malaria parasites, which have evolved resistance to almost all drugs. There is therefore urgent need for new drugs with novel mechanisms of action. Drugs targeting the liver stage malaria parasite before it infects the blood may provide the upside of antimalarial immunity. Previously, we showed that a new class of antimalarial drugs targeting the aspartyl proteases plasmepsin IX and X kill liver parasites just before they establish a blood infection, thus providing prophylaxis (Favuzza et al Cell Host & Microbe 2020). Here, we show that such late liver stage death and prophylaxis confers long-lived protective immunity to reinfection. Mice infected with live malaria sporozoites from mosquitoes were cured using antimalarials targeting plasmepsins IX and X and subsequently developed sterilizing immunity against malaria lasting 21 months that was dependent on both T cells and humoral immune responses. The inclusion of late liver stage-active drugs in future prevention programs has exciting implications for delivering SMC with the added benefit of T cell-mediated vaccination/boosting against locally circulating, heterologous, mosquito-borne human malaria parasites in endemic regions.