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Hepatocellular carcinoma is one of the most common primary malignant tumors of the digestive system. Compound 5-chloro-N′-(2,4-dimethoxybenzylidene)-1H-indole-2-carbohydrazide (IHZ-1/ZJQ-24) is a novel indole hydrazide derivative. In a recent study, we demonstrated that IHZ-1 inhibits tumor growth and induces cell apoptosis through inhibiting the kinase activity of mTORC1 without activation of AKT, which is associated with JNK/IRS-1 activation. However, the impact and mechanisms of JNK activation by IHZ-1 in hepatocellular carcinoma remains entirely unknown. Here, we find that IHZ-1 increases the generation of intracellular ROS and enhances autophagy. The phosphorylation of JNK induced by IHZ-1 was reversed by the decreased ROS level. Moreover, inhibition of ROS/JNK or autophagy equally attenuated apoptotic effect induced by IHZ-1. Our findings suggest that the activation of JNK by IHZ-1 treatment is dependent on the generation of ROS that mediates apoptosis and autophagy in hepatocellular carcinoma.