Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and durable therapeutic options remain limited. Ferroptosis has emerged as a therapeutically exploitable vulnerability in HCC. Here, we characterized the anticancer activity of decursin, a natural coumarin derived from Angelica gigas . Decursin reduced the viability and long-term proliferative capacity of HepG2 and Huh7 cells in a dose-dependent manner, with half-maximal inhibitory concentration (IC ₅₀ ) values of approximately 100 μM and 150 μM, respectively. It also impaired migratory and invasive behaviors while inducing oxidative stress, including lipid peroxidation and glutathione depletion, which are hallmarks of ferroptosis. Integrated transcriptomic and metabolomic profiling revealed a broad disruption of redox and glutathione metabolism, converging on the attenuation of the NRF2–GPX4 antioxidant axis. Computational target prediction and docking further suggested that decursin may influence iron-handling pathways involving SLC11A2, although this relationship requires further validation. In vivo , decursin significantly inhibited tumor growth in xenograft models and reduced NRF2/GPX4 expression. Notably, decursin retained its efficacy in sorafenib-resistant HCC cells. Collectively, these findings identify decursin as a ferroptosis-inducing agent with therapeutic potential in HCC.