An antiplasmodial activity-guided isolation was carried out on the dichloromethane extract of Tithonia diversifolia dried leaves. A total of five germacranolide type sesquiterpene lactones and a new flavonol, 3,6-dihydroxy-2-(4′-hydroxyphenyl)-7-methoxy-4H-chromen-4-one, were isolated. The flavonol reported an IC₅₀ above 6.00 µM against the chloroquine sensitive strain, NF54. The antimalarial activity of the Tithonia diversifolia dichloromethane leaf extract was attributed to orizabin and tagitinin C.