RAB18, a member of the Ras family, has been suggested to play a critical role in multiple biological process. However, its functions in the development of hepatocellular carcinoma (HCC) remain unknown. In the present study, the expression and biological role of RAB18 in HCC were investigated. Results showed that the expression level of RAB18 was significantly increased in HCC tissue specimens and HCC cell lines. Kaplan-Meier survival analysis showed that high RAB18 expression was correlated with poor overall survival compared to those with low RAB18 expression. These results were further confirmed by analyses in the Cancer Genome Atlas (TCGA) database. Specific knockdown of RAB18 expression inhibited proliferation and clone formation of HCC in vitro. Western blot analyses showed that CCND1 was suppressed, and p21 and p27 were substantially upregulated in RAB18 knockdown HCC cells. Furthermore, we also observed that knockdown of RAB18 expression suppressed the migration and invasion of HCC cells and reversed expression of epithelial-mesenchymal transition (EMT)-related markers. Interestingly, the primary and xenograft tumor mouse models showed that RAB18 knockdown significantly reduced in vivo tumorigenesis and metastasis in nude mice. These results revealed that RAB18 was correlated with poor clinical outcomes and facilitated HCC progression via promotion of HCC cell proliferation and metastasis. These findings suggest that RAB18 may be a prognostic biomarker and potential therapeutic target in patients with HCC.