Sushi repeat-containing protein X-linked 2 (SRPX2), a novel chondroitin sulfate proteoglycan, is overexpressed in human cancer. Recent studies have reported that SRPX2 overexpression is observed in gastrointestinal cancer, and promotes migration and invasion of cancer cells. While, the clinical significance and biological function of SRPX2 remain rarely known in hepatocellular carcinoma (HCC). Here, we found that the levels of SRPX2 in HCC tissues were notably overexpressed compared to non-cancerous specimens. Accordingly, the levels of SRPX2 were obviously up-regulated in HCC cells compared with LO2 cells. The positive expression of SRPX2 was prominently correlated with venous infiltration and advanced TNM tumor stage. Furthermore, SRPX2 expression acted as an independent prognostic marker for HCC patients. SRPX2 knockdown prominently inhibited the invasion and migration of HCCLM3 cells, while SRPX2 restoration enhanced these cellular biological behaviors of Hep3B cells in vitro. Moreover, SRPX2 knockdown suppressed pulmonary metastasis of HCCLM3 cells in nude mice. Mechanically, SRPX2 knockdown reduced the levels of phosphorylated focal adhesion kinase (p-FAK), p-AKT, matrix metallopeptidase 2 (MMP2) and MMP9 in HCCLM3 cells. In turn, SRPX2 overexpression promoted the activation of FAK/AKT pathway and increased MMP2/9 expression in Hep3B cells. Thus, SRPX2 contributes to migration and invasion of HCC cells probably by targeting FAK/AKT pathway-mediated MMP2/9 expression. SRPX2 potentially acts as an independent prognostic predictor and a drug-target for HCC patients.