ABSTRACTMalaria treatments resulted in the decline of the deadliestPlasmodium falciparumglobally while species, such asP. ovale, infections have been increasingly detected across sub-Saharan Africa. Currently, no experimental drug sensitivity data are available to guide effective treatment and management ofP. ovaleinfections, which is necessary for effective malaria elimination. We conducted a prospective study to evaluateP. ovaleepidemiology over 1 year and determinedex vivosusceptibility of the field isolates to existing and lead advanced discovery antimalarial drugs. We report that whileP. falciparumdominated both symptomatic and asymptomatic malaria cases,P. ovalein mono or co-infections caused 7.16% of symptomatic malaria. Frontline antimalarials artesunate and lumefantrine inhibitedP. ovaleas potently asP. falciparum. Chloroquine, which has been withdrawn in Ghana, was also highly inhibitory against bothP. ovaleandP. falciparum. In addition,P. ovaleandP. falciparumdisplayed high susceptibility to quinine, comparable to levels observed with chloroquine. Pyrimethamine, which is a major drug for disease massive prevention, also showed great inhibition ofP. ovale, comparable to effects onP. falciparum. Furthermore, we identified strong inhibition ofP. ovaleusing GNF179, a close analogue of KAF156 imidazolopiperazines, which is a novel class of antimalarial drugs currently in clinical phase II testing. We further demonstrated that thePlasmodiumphosphatidylinositol-4-OH kinase (PI4K)-specific inhibitor, KDU691, is highly inhibitory againstP. ovaleandP. falciparumfield isolates. Our data indicated that existing and lead advanced discovery antimalarial drugs are suitable for the treatment ofP. ovaleinfections in Ghana.IMPORTANCECurrent malaria control and elimination tools such as drug treatments are not specifically targetingP.ovale.P. ovalecan form hypnozoite and cause relapsing malaria.P. ovaleis the third most dominant species in Africa and requires radical cure treatment given that it can form liver dormant forms called hypnozoites that escape all safe treatments. The inappropriate treatment ofP. ovalewould sustain its transmission in Africa where the medical need is the greatest. This is a hurdle for successful malaria control and elimination. Here, we provided experiment data that were lacking to guideP. ovaletreatment and disease control policy makers using reference antimalarial drugs. We also provided key experimental data for 2 clinical candidate drugs that can be used for prioritization selection of lead candidate’s identification for clinical development.