Background: Tanshinone IIA, one of the main ingredients of Danshen, is used to treat hepatocellular carcinoma (HCC). However, potential targets of the molecule in the therapy of HCC are unknown. Methods: In this study, we collected the tanshinone IIA targets from public databases for investigation. We screened differentially expressed genes (DEGs) across HCC and normal tissues using mRNA expression profiles from The Cancer Genome Atlas (TCGA). Univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) Cox regression models were used to identify and construct the prognostic gene signature. Results: Finally, we discovered common genes across tanshinone IIA targets and HCC DEGs. We reported Fatty acid binding protein-6 (FABP6), Polo-like Kinase 1 (PLK1), deoxythymidylate kinase (DTYMK), Uridine Cytidine Kinase 2 (UCK2), Enhancer of Zeste Homolog 2 (EZH2), and Cytochrome P450 2C9 (CYP2C9) as components of a gene signature. The six-gene signature's prognostic ability was evaluated using the Kaplan-Meier curve, time-dependent receiver operating characteristic (ROC), multivariate Cox regression analysis, and the nomogram. The mRNA level and protein expression of UCK2 were experimentally validated after treatment with different concentrations of tanshinone IIA in HEPG2 cells. CIBERSORTx, TIMER2.0, and GEPIA2 tools were employed to explore the relationship between the prognostic signature and immune cell infiltration. Conclusion: We established a six-gene signature as a reliable model with significant therapeutic possibility for prognosis and overall survival estimation in HCC patients, which might also benefit medical decision-making for appropriate treatment.