Increasing studies have indicated that long noncoding RNAs (lncRNAs) exert important roles in hepatocellular carcinoma (HCC). Therefore, it is of great significance to identify the dysregulated lncRNAs in HCC. According to the previous reports, it has been suggested that DiGeorge syndrome critical region gene 5 (DGCR5) might participate in HCC and can serve as potential biomarker for HCC. In our current study, we concentrated on the biological function and roles of lncRNA-DGCR5 in HCC. It was indicated that DGCR5 was decreased in HCC tissues and HCC cells including HepG2, Hep3B, MHCC-97L, SNU-449, and SNU-182 cells compared with the normal human liver cell line LO2. Overexpression of DGCR5 was able to restrain HCC growth, migration, and invasion capacity in HepG2 and SNU-449 cells. In addition, whether lncRNA-DGCR5 can regulate Wnt/beta-catenin pathway during HCC progression is unclear. In our study, it was found that upregulation of DGCR5 inactivated Wnt signaling pathway through inhibiting beta-catenin, cyclin D1 and increasing GSK-3 beta levels. Subsequently, in vivo tumor xenografts were established using HepG2 cells to investigate the function of DGCR5 in HCC development. Inconsistent with the in vitro findings, increase of DGCR5 dramatically suppressed HCC tumor progression in vivo. Taken these together, it was uncovered in our research that DGCR5 could play tumor suppressive role by targeting Wnt signaling in HCC progression.