A novel series of 3-cinnamoyl-4-hydroxy-2Hchromen-2-ones were designed, synthesized and screened for antiplasmodial activity. Eleven compounds of the series exhibited micromolar potency against chloroquine sensitive and chloroquine resistant strains. The most potent compound 4-hydroxy-3-(3-(4- nitrophenyl)acryloyl)-2Hchromen-2-one showed inhibitory potency (IC 50) of 3.1 and 4 μg/ml against chloroquine sensitive and chloroquine resistant strains, respectively. A structure activity relationship study was performed by correlating the effect of substituents with the antimalarial activity of the title compounds. The novel 3-cinnamoyl-4-hydroxy- 2H-chromen-2-ones reported here should be good lead for further development of antimalarial agents that can overcome resistance.