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Esophageal cancer (EC) is one of the most fatal malignancies worldwide. Dehydrocostus lactone (DHL) derived from the dried roots of Saussurea costus (Falc.) Lipech is a sesquiterpene lactone compound that exerts anticancer activities. In this study, DHL was obtained to evaluate its anti-esophageal cancer ability and underlying mechanism in vitro and in vivo. DHL inhibited the proliferation and migration of Eca109 and KYSE150 esophageal cancer cells in a time- and dose-dependent manner. Moreover, it inhibited the growth of Eca109 tumor xenografts in a dose-dependent manner with no significant signs of toxicity in the organs of nude mice. Mechanistically, treatment with DHL could significantly activate reactive oxygen species (ROS) in cells, leading to mitochondrial damage, and inducing apoptosis and autophagy. The ROS inhibitor N-acetyl-L-cysteine (NAC) inhibited DHL-induced apoptosis and autophagy. The pancaspase inhibitor Z-VAD-FMK diminished DHL-induced autophagy, but the autophagy inhibitor 3-methyladenine (3-MA) had no effect on DHL-induced apoptosis. Western blot analysis results indicated that the PI3K/Akt/Bad pathway participated in this process. In conclusion, DHL inhibits the proliferation of esophageal cancer cells through ROS-mediated apoptosis and autophagy in vivo and in vitro. All results suggest that DHL can be considered a potential chemotherapeutic drug for esophageal cancer.