Hepatocellular carcinoma (HCC) remains a disease with a high mortality rate, and the treatment for HCC remains limited. It is necessary to develop efficient and low toxicity drugs for the clinical treatment of HCC. Lenalidomide is a novel analogue of thalidomide and has anti‑inflammatory, immunomodulatory and anti‑angiogenic effects. The current study investigated the inhibitory effect against HCC cells of lenalidomide and thalidomide. The MTT assay was used to determine the cytotoxicity of lenalidomide and thalidomide, and morphological changes were observed by fluorescence microscopy. Caspase and VEGF protein expression were measured by ELISA analysis and western blotting. It was identified that treatment of cells with lenalidomide and thalidomide led to a dose‑dependent inhibition of cell proliferation, and the two drugs were able to induce cells apoptosis and inhibit VEGF expression in HCC cells. In addition, lenalidomide was identified to exhibit greater effects than thalidomide at the same concentration. In conclusion, the results indicated that lenalidomide induces apoptosis and inhibits angiogenesis in HCC cells via caspase‑3 and VEGF pathway, and these may provide a potential perspective for lenalidomide's application in clinical.