The involvement of long non-coding RNA (LncRNAs) in HCC development has been widely recognized in recent decades. LncRNA small nucleolar RNA host gene 5 (SNHG5) has been identified to be implicated in the development of many tumors, and this study aimed to explore the role of SNHG5 in HCC tumorigenesis. The expression levels of SNHG5, miR-363-3p, and Ring Finger Protein 38 (RNF38) were measured by using quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) or Western blot assay, respectively. Cell proliferation was analyzed by MTT assay. Flow cytometry was used to investigate cell apoptosis. Cell migration and invasion abilities were detected by transwell assay. The relationship among SNHG5, miR-363-3p, and RNF38 was confirmed using bioinformatics analysis and Luciferase reporter assay. The expression of SNHG5 and RNF38 was elevated in HCC tissues and cell lines, and highly expressed SNHG5 and RNF38 could induce apoptosis and repress proliferation, migration, as well as invasion in HCC cells. Further investigations showed that SNHG5 might act as a competing endogenous RNA of miR-26a-5p and thereby cause the derepression of the downstream target RNF38. Moreover, rescue experiments indicated that SNHG5 silence inhibited the progression of HCC cells by regulating miR-363-3p, and the facilitated effects of RNF38 in the progression of HCC cells were regulated by miR-363-3p. LncRNA SNHG5 may promote human HCC progression by regulating the miR-363-3p/RNF38 axis, providing a novel insight into the pathogenesis of HCC and therapeutic strategy for HCC treatment.