Metabolic reprogramming for adaptation to the tumor microenvironment is recognized as a hallmark of cancer. Although many altered metabolic genes have been reported to be associated with tumor pathological processes, systematic analysis of metabolic genes implicated in hepatocellular carcinoma prognosis remains rare. The aim of this study was to identify key metabolic genes related to hepatocellular carcinoma, and to explore their clinical significance. We downloaded mRNA expression profiles and clinical hepatocellular carcinoma data from The Cancer Genome Atlas database to explore the prognostic roles of metabolic genes. Five prognosis-associated metabolic genes, including POLA1, UCK2, ACYP1, ENTPD2, and TXNRD1, were screened via univariate Cox regression analysis and a LASSO Cox regression model, which divided patients into high- and low-risk groups. Furthermore, gene set enrichment analysis revealed that significantly-enriched gene ontology terms and pathways involving high-risk patients were focused on regulation of nucleic and fatty acid metabolism. Taken together, our study identified five metabolic genes related to survival, which can be used to predict the prognosis of patients with hepatocellular carcinoma. These genes may play essential roles in metabolic microenvironment regulation, and represent potentially important candidate targets in metabolic therapy.