Reactive oxygen species- (ROS-) mediated autophagy physiologically contributes to management of cell homeostasis in response to mild oxidative stress. Cancer cells typically engage autophagy downstream of ROS signaling derived from hypoxia and starvation, which are harsh environmental conditions that need to be faced for cancer development and progression. Hepatocellular carcinoma (HCC) is a solid tumor for which several environmental risk factors, particularly viral infections and alcohol abuse, have been shown to promote carcinogenesis via augmentation of oxidative stress. In addition, ROS burst in HCC cells frequently takes place after administration of therapeutic compounds that promote apoptotic cell death or even autophagic cell death. The interplay between ROS and autophagy (i) in the disposal of dysfunctional mitochondria via mitophagy, as a tumor suppressor mechanism, or (ii) in the cell survival adaptive response elicited by chemotherapeutic interventions, as a tumor-promoting event, will be depicted in this review in relation to HCC development and progression.