A series of N1 -{4-[(10S)-dihydroartemisinin-10-oxyl]}phenylmethylene-N2 -(2-methylquinoline-4-yl) hydrazine derivatives 9a–9n possessing 4-quinolylhydrazone and artemisinin cores were herein synthesized and evaluated for their activities against cysteine protease falcipain-2 of Plasmodium falciparum. The structures were clearly confirmed by elemental analysis, 1 H NMR, and mass spectra. The pharmacological results indicated that all compounds showed excellent activity against recombinant falcipain-2 (IC50 = 0.15–2.28 lM). The best one of this series was compound 9d (IC50 = 0.15 lM). The molecular docking results showed that the compound 9d made close contact with the key active site of cysteine protease falcipain-2.