Deregulation of autophagy is proposed to play a key pathogenic role in hepatocellular carcinoma (HCC), the most common primary malignancy of the liver and the third leading cause of cancer death. Autophagy is an evolutionarily conserved catabolic process activated to degrade and recycle cell's components. Under stress conditions, such as oxidative stress and nutrient deprivation, autophagy is an essential survival pathway that operates in harmony with other stress response pathways. These include the redox-sensitive transcription complex Nrf2-Keap1 that controls groups of genes with roles in detoxification and antioxidant processes, intermediary metabolism, and cell cycle regulation. Recently, a functional association between a dysfunctional autophagy and Nrf2 pathway activation has been identified in HCC. This appears to occur through the physical interaction of the autophagy adaptor p62 with the Nrf2 inhibitor Keap1, thus leading to increased stabilization and transcriptional activity of Nrf2, a key event in reprogramming metabolic and stress response pathways of proliferating hepatocarcinoma cells. These emerging molecular mechanisms and the therapeutic perspective of targeting Nrf2-p62 interaction in HCC are discussed in this paper along with the prognostic value of autophagy in this type of cancer.