Tetramethylpyrazine is a bioactive compound found in Chinese black vinegar. This work is to investigate the potential effects of tetramethylpyrazine on intracellular cholesterol modulation in HepG2 cells. The results demonstrated that tetramethylpyrazine can induce intracellular cholesterol efflux. Tetramethylpyrazine may also improve endothelial function through its antioxidant effects by inhibiting reactive oxygen species levels and increasing the antioxidant enzymes superoxide dismutase and catalase. Tetramethylpyrazine increased liver X receptor and peroxisome proliferator-activated receptor gene expression in HepG2 cells. Protein expression of ATP-binding cassette transporter 1 was up-regulated in a dose-dependent manner (P < 0.05). The biological significance of tetramethylpyrazine may involve hypolipidemic effects via modulation of intracellular cholesterol efflux, ROS inhibition, increases in SOD and CAT activities, and direct regulation of PPAR and LXR gene expression. Tetramethylpyrazine may improve lipid profiles by elevating the PPARγ-LXRα-ABCA1 pathway.