BACKGROUND AND PURPOSE In this study, we compared the different effect of Dimethyl-2-ketoglutarate (DMKG) on energy metabolism, autophagy, and apoptosis between parental and doxorubicin-resistant liver cancer cell lines. EXPERIMENTAL APPROACH In the energy metabolism section, cell viability, adenosine triphosphate (ATP) level, doxorubicin (DOX) content, energy metabolism phenotype, and enzymes expression were measured. In the autophagy part, autophagy vesicles were observed, enzymes expression and cell viability were detected. Apoptosis rate and expression of enzymes were detected in the apoptosis part. KEY RESULTS DMKG can directly act on ATP synthase and prolyl hydroxylase, affecting the cellular oxidative phosphorylation and glycolysis levels, respectively, in both SMMC-7721 and SMMC-7721/DOX cells. However, its practical effects depend on the function of the mitochondrial malate-aspartate shuttle. Furthermore, ATP-reduced cell autophagy had partial anti-apoptotic effects in SMMC-7721 cells, which is an important reason for the weak inhibition of cell viability observed at low doses of DMKG. In contrast, DMKG showed no significant effect on autophagy but a high cell death rate in SMMC-7721/DOX cells. Induced high expression levels of p-AMPK, p-mTOR, and Bcl-2 could inhibit DMKG-induced apoptosis in SMMC-7721 cells. However, activation of Caspase-3 was the most important molecular effect that was observed in relation to the DMKG-induced apoptosis in SMMC-7721/DOX cells. CONCLUSIONS AND IMPLICATIONS These results suggest that inhibition of energy metabolism can reduce the effects of autophagy in DOX resistant cells, which could improve the therapeutic outcomes and reverse the resistance to chemotherapeutic drugs. This article provides a new idea and method for reversing tumor resistance.