Hepatocellular carcinoma (HCC), one of the most common malignant cancers with a low 5-year survival rate, is the third leading cause of cancer-related deaths worldwide. The finding of novel agents and strategies for the treatment of HCC is an urgent need. Sesquiterpene lactones (SLs) have attracted extensive attention because of their potent antitumor activity. In this study, a new series of SL derivatives (-) were synthesized using epimers and as parent molecules, isolated from , and evaluated for their anti-HCC activity. Furthermore, the structures of , , and were confirmed by X-ray single-crystal diffraction analyses. The cytotoxic activities of - on two HCC cell lines, including HepG2 and Huh7, were evaluated using the CCK-8 assay. Among them, compound exhibited the best activity against the HepG2 and Huh7 cell lines. Further studies showed that induced cell apoptosis, arrested the cell cycle at the S phase, and induced the inhibition of cell proliferation and migration in HepG2 and Huh7. In addition, absorption, distribution, metabolism, and excretion (ADME) properties prediction showed that may possess the properties to be a drug candidate. Thus, may be a promising lead compound for the treatment of HCC.