Hepatocellular carcinoma (HCC) is the most common fatal cancer worldwide, patients with HCC have a high mortality rate and poor prognosis. PANoptosis is a novel discovery of programmed cell death associated with cancer development. However, the role of PANoptosis in HCC remains obscure. In this study, we enrolled 274 PANoptosis-related genes (PANRGs) and screened 8 genes to set up a prognostic model. A previous scoring system calculated PANscore was utilized to quantify the individual risk level of each HCC patient, and the reliability of the prognostic model has been validated in an external cohort. Nomogram constructed with PANscore and clinical characteristics were used to optimize individualized treatment for each patient. Single-cell analysis revealed a PANoptosis model associated with tumor immune cell infiltration, particularly natural killer (NK) cells. Further exploration of hub genes and assessment of the prognostic role of these 4 hub genes in HCC by quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC). In conclusion, we evaluated a PANoptosis-based prognostic model as a potential prognostic biomarker for HCC patients.