In spite of an initially promising anti-tumor activity, oxaliplatin-based combinatorial treatments can eventually result in a tumor resistance response. In this study we aimed to understand the role of autophagy in HCC cell resistance to oxaliplatin and to discuss its potential therapeutic implication. We found that exposure to oxaliplatin induced a significant increase in LC3 lipidation and subsequent LC3 puncta formation. While the proliferation of HCC cells was inhibited upon oxaliplatin exposure, inhibition of autophagy by ATG7 interference and chloroquine pre-treatment further increased the sensitivity to chemotherapy. Meanwhile, the oxaliplatin-induced apoptotic cell death was significantly enhanced. These results suggest that autophagy may function importantly in HepG2 cell resistance to oxaliplatin. Intriguingly, the resistance could be recovered apparently by inhibition of autophagy. This also points to the potential therapy for hepatoma by perturbing autophagy.