The diabetes drug metformin has recently been shown to possess anti-cancer properties when used with other chemotherapeutic drugs. However, detailed mechanisms by which metformin improves cancer treatment are poorly understood. Here we provide evidence in HepG2 hepatocellular carcinoma cells that metformin sensitizes cisplatin-resistant HepG2 cells (HepG2/DDP) through increasing cellular glycolysis and suppressing Nrf2-dependent transcription. We show that metformin increases glucose uptake and enhances glucose metabolism through glycolytic pathway, resulting in elevated concentrations of intracellular NADPH and lactate. Consistently, high glucose medium suppresses Nrf2-dependent transcription and sensitizes HepG2/DDP cells to cisplatin. Elevated glycolysis was required for metformin to regulate Nrf2-dependent transcription and cisplatin sensitivity, as inhibition of glycolysis with 2-Deoxy-D-glucose (2-DG) significantly mitigates the beneficial effect of metformin. Together, our study has revealed an important biological process and gene transcriptional program underlying the beneficial effect of metformin on reducing chemo-resistance in HepG2 cells and provided new information on improving chemotherapy of liver cancers.