Hepatocellular carcinoma (HCC) is a common, prevalent malignancy. Its poor prognosis is mainly related to high rate of diagnosis in non-curable stages, in which patients are suitable for palliative treatment. Placenta-specific 8 (PLAC8), also known as Onzin, is a small, highly conserved, cysteine-rich protein. In current study, we found that PLAC8 is prominently decreased in HCC tissues compared with adjacent tissues and patients with low level of PLAC8 suffered a poor prognosis. In addition, cellular function assays demonstrate that down-regulated PLAC8 promotes cell viability, proliferation and tumor formation both in vitro and in vivo. Furthermore, we validate that down-regulated PLAC8 enhances the activity of PI3K/Akt/GSK3β and Wnt/β-catenin signaling to promote cell proliferation. Moreover, we proved that highly expressed miR-185-5p targets PLAC8 in HCC tissues. In conclusion, our findings enlarged our knowledge about the roles of PLAC8 in HCC progression and miR-185-5p/PLAC8/β-catenin axis might be a novel pathway for HCC treatment.