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Abstract Background CELSR2 is postulated to be a receptor involved in contact-mediated communication; however, the specific function of this particular member has not been determined in hepatocellular carcinoma (HCC). Methods Here, we explored the expression and function of CELSR2 in HCC patients through data mining and examined the results using clinical samples and in vitro experiments. Results It was found that CELSR2 mRNA and protein expression levels were significantly higher in cancerous tissue than in normal tissue. The increased mRNA expression of CELSR2 was significantly associated with overall survival (OS) in HCC patients. Moreover, the genetic alteration rate of CELSR2 gene in HCC can reach 8%, and these alterations would deeply influence its neighboring genes, then jointly affecting the occurrence and development of tumor through cell adhesion and numerous common carcinogenic pathways. Our in vitro results indicated that the depletion of CELSR2 inhibited liver cancer cell proliferation and invasion. Univariate and multivariate Cox regression analyses showed that CELSR2 could be viewed as an independent risk factor for HCC patients. Conclusions This study demonstrated that data mining could efficiently reveal the roles of CELSR2 in HCC and its potential regulatory networks. The CELSR2 protein level may serve as a novel prognostic biomarker for HCC.