Objective: To investigate the effect of blueberry anthocyanin on apoptosis and histone acetylation modification in human hepatocellular carcinoma HepG2 cells. Methods: The anthocyanin was extracted from blueberries native to Majiang county of Guizhou province, and the content determination and identification of anthocyanin were performed by high performance liquid chromatography. In HepG2 cells after incubation with blueberry anthocyanin, the morphological changes, cell proliferation and apoptosis as well as the acetylation of histone H3K9, H3K14, H3K18, and H3K27 were observed. Results: Compared with untreated control HepG2 cells, in HepG2 cells after incubation with different concentrations of blueberry anthocyanin (50, 100, 150, 200, and 300 μg/mL) for 48 h, the cell volume was obviously reduced, proliferation was significantly inhibited (all P<0.05) and apoptosis was remarkably increased, and all these effects were increased with increasing concentration of blueberry anthocyanin; the acetylation of histone H3K9, H3K14, H3K18 and H3K27 were significantly enhanced in HepG2 after treatment with different concentrations of blueberry anthocyanin (50, 100 and 200 μg/mL) for 48 h (all P<0.05), with a concentration-dependent manner. Conclusion: Blueberry anthocyanin has inhibitory effect on the proliferation of HepG2 cells, and the mechanism may probably be related to its enhancing histone acetylation and thereby promoting cell apoptosis.