Long noncoding RNA OIP5-AS1 has been observed to be increased in several cancers, however, its role and biological mechanism was poorly understood in HCC. Currently, we found OIP5-AS1 expression was upregulated in HCC cells compared with normal human liver cells. Knockdown of OIP5-AS1 suppressed HCC cell proliferation, induced cells cycle arrest and cells apoptosis. In addition, HCC cell migration and invasion capacity in vitro were also inhibited by OIP5-AS1 inhibition. Bioinformatics analysis revealed OIP5-AS1 could interact with miR-363-3p, thereby repressing HCC development. We also observed miR-363-3p was significantly decreased in HCC cells and overexpression of miR-363-3p repressed HCC progression. The correlation between OIP5-AS1 and miR-363-3p was confirmed by performing RIP assay and RNA pull-down assay. Subsequently, SOX4 was predicted as a target of miR-363-3p and miR-363-3p modulated SOX4 levels negatively in vitro. Apart from these, in vivo experiments established that OIP5-AS1 can suppress HCC development through regulating miR-363-3p and SOX4. Collectively, these demonstrated that OIP5-AS1 was involved in HCC progression via targeting miR-363-3p and SOX4. OIP5-AS1 can act as a novel candidate for HCC diagnosis, prognosis, and therapy.