Background <p>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with metabolic reprogramming playing a critical role in its progression. Bile acid metabolism has emerged as a key pathway in hepatocarcinogenesis, yet its comprehensive role in HCC remains poorly understood. This study aims to systematically investigate the dysregulation of bile acid metabolism in HCC and its clinical implications.</p> Methods <p>We performed gene set enrichment analysis (GSEA), genomic alteration analysis, transcriptional profiling, and DNA methylation analysis using transcriptomic and genomic data from the TCGA cohort. A bile acid metabolism signature was developed using single-sample GSEA (ssGSEA), and its prognostic value was assessed through Kaplan–Meier survival and Cox regression analyses. Immune cell infiltration and associations with immunotherapy and chemotherapy response were also evaluated.</p> Results <p>Using training data from 368 HCC patients and validation cohorts (<i>n</i> = 221), significant dysregulation of bile acid metabolism was observed, with distinct pathway activation across clinical subgroups (<i>P</i> &lt; 0.05). Genomic alterations, including mutations and copy number variations, were identified in key bile acid metabolism-related genes. The bile acid metabolism signature was strongly associated with overall survival and tumor stage (<i>P</i> &lt; 0.05). Immune cell infiltration patterns varied significantly between high and low bile acid metabolism groups, suggesting a role in shaping the tumor immune microenvironment. However, no significant association was found between the signature and immunotherapy response.</p> Conclusion <p>This study highlights the critical role of bile acid metabolism in HCC progression, with potential implications for prognosis and therapeutic targeting. The bile acid metabolism signature serves as a robust prognostic indicator, offering insights into personalized treatment strategies.</p>