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Background and Objective: Pyrazolone derivatives were reported to have a potent cytotoxicity against some tumor cells. In the present study, we evaluated the cytotoxic activity of a series of pyrazolone derivatives against four human tumor cell lines including HepG2, OVCAR3, KB, and multidrug resistance (MDR) KBv200 cell lines in vitro and in vivo. Additionally, the structure-activity relationships of these compounds were discussed. Methods: To analyze the antiproliferative potential of the synthesized compounds against several human tumor cell lines, the 50% inhibitory concentration (IC50) values were determined by Mtt assay. Besides, the KBv200 cell xenograft experimental model was established and the sensitivity to the pyrazolone compounds was compared between drug-sensitive parental KB cells and MDR KBv200 cells. Results: Of 13 compounds screened, compound 9 presented remarkable anticancer effects, of which IC50 values were (3.24 ± 0.28), (2.58 ± 0.61), (3.81 ± 0.02), and (3.45 ± 0.03) μg/mL in HepG2, OVCAR3, KB and MDR KBv200 cells, respectively (P ＞ 0.05). Furthermore, compound 9 effectively inhibited tumor growth of KBv200 cell xenografts in vivo, the inhibition ratio was 25.37%, 38.43%, and 47.50% for 1.5 mg/kg, 3 mg/kg, and 6 mg/kg of compound 9 groups,respectively. Conclusion: Compound 9 was the most promising antitumor agent in this study.