Sesquiterpenoid tagitinin C, present in Tithonia diversifolia leaves, has been known to have anti-hepatoma properties. Therefore, we investigated the anti-metastatic potential of tagitinin C in xenograft models of hepatocellular carcinoma (HCC). We isolated tagitinin C from a methanolic extract of the leaves of T. diversifolia. HepG-2 and Huh 7 hepatoma cells were treated with tagitinin C, and cell viability, migration, and matrix metalloproteinase (MPP) activity were assessed using the 3-(4,5-dimethylthiozol-2-yl)-2,5-diphenyltetrazolium bromide assay, scratch migration assay, and MMP activity assay, respectively. We used magnetic resonance spectroscopy to determine the tumorigenicity of xenografts inoculated with Hep-G2 and Huh 7 cells. Tagitinin C was cytotoxic against Hep-G2 and Huh 7 cells, with IC₅₀ values of 2.0 ± 0.1 µg/mL and 1.2 ± 0.1 µg/mL, respectively, and it showed an anti-metastatic effect in vitro. Additionally, MRS assays revealed that tagitinin C (15 g/mouse/day) reduced the tumorigenicity of Hep-G2 and Huh 7 cell xenografts. Tagitinin C demonstrated significant antitumor and anti-metastatic activity in the two human hepatoma cell lines. Tagitinin C might be used as an alternative or auxiliary therapy for the treatment of HCC, and its effect should be further investigated in clinical settings.