Resveratrol, a natural polyphenolic phytochemical, has received considerable attention due to its potential chemopreventive and chemotherapeutic properties. In the present study, we first evaluated the growth-inhibitory effect of resveratrol on HepG2 cells and explored the underlying molecular mechanisms. Resveratrol inhibited proliferation and induced apoptosis in HepG2 cells via activation of caspase-9 and caspase-3, upregulation of the Bax/Bcl-2 ratio and induction of p53 expression. Cell cycle analysis demonstrated that resveratrol arrested cell cycle progression in the G1 and S phase. We further focused on the combination of matrine, a natural component extracted from the traditional Chinese medical herb Sophora flavescens Ait., as a mechanism to potentiate the growth-inhibitory effect of resveratrol on HepG2 cells. Both MTT and colony formation assay results indicated that the combined treatment of resveratrol and matrine exhibited a synergistic antiproliferative effect. In addition, resveratrol-induced apoptosis was significantly enhanced by matrine, which could be attributed to activation of caspase-3 and caspase-9, downregulation of survivin, induction of reactive oxygen species (ROS) generation and disruption of mitochondria membrane potential (Δψm). Our findings suggest that the combination treatment of resveratrol and matrine is a promising novel anticancer strategy for liver cancer; it also provides new insights into the mechanisms of combined therapy.