Hepatocellular carcinoma is the most common type of liver cancer. The risk of hepatocellular carcinoma for type 2 diabetic patients is greater than that for non-diabetic individuals although the mechanism is unclear. The cancer suppressor resveratrol inhibits cancer cell proliferation partly through the STAT3 signaling pathway. However, the effects of resveratrol on STAT3 in high glucose-exposed HepG2 cells and the role of SIRT1 are not clear to date. The aim of the present study was to investigate the effects of resveratrol on STAT3 and SIRT1 regarding the proliferation of high glucose-exposed HepG2 cells. HepG2 cells were cultured in DMEM containing glucose (2.8, 5.5 and 25 mM) and resveratrol (0, 10 and 100 µM). HepG2 cell proliferation and viability were analyzed by MTT assays. The levels of p-STAT3 and SIRT1 were analyzed by western blotting, and RT-PCR methods were used to detect the transcription levels of cyclin B1, cyclin D1, VEGF and MMP-9. SIRT1-specific short-interfering RNA was used to investigate the role of SIRT1 in p-STAT3 signaling. A high glucose concentration (25 mM) induced HepG2 cell proliferation. This effect was suppressed by resveratrol (100 µM), and the effect on the p-STAT3 signaling pathway was found to be SIRT1-dependent. Our findings may provide new insights into the mechanism by which resveratrol suppresses HepG2 cell proliferation under conditions of high glucose. Furthermore, this information may provide the basis for a novel therapeutic strategy for hepatocellular carcinoma patients suffering from either diabetes or hyperglycemia.