Hepatocellular carcinoma (HCC) is the most common type of liver cancer with high mortality. Identifying key molecules involved in the regulation of HCC development is of great clinical significance. SOX11 is a transcription factor belonging to group C of Sry-related high mobility group box family whose abnormal expression is frequently seen in many kinds of human cancers. Here, we noted that the expression of SOX11 was decreased in human HCC tumors compared with that in matched normal tissues. Overexpression of SOX11 promoted growth inhibition and apoptosis in HCC cell line HuH-7. Mechanistically, SOX11 enhanced the expression of nemo-like kinase and the phosphorylation of TCF4, thereby blunting the activation of oncogenic Wnt/β-catenin signaling pathway in HuH-7 cells. Finally, SOX11 was also found to sensitize HuH-7 cells to chemotherapy drugs cisplatin and 5-fluorouraci. Therefore, our study identifies SOX11 as a potential tumor suppressor in HCC and may hopefully be beneficial for the clinical diagnosis or treatment of HCC.