BACKGROUND: In recent years, therapeutic strategies for liver cancer have been continuously evolving, with transarterial chemoembolization (TACE) being widely applied. Although TACE has demonstrated good short-term efficacy, long-term prognosis remains a challenge. This study aimed to investigate the clinical efficacy and safety of TACE combined with tyrosine kinase inhibitors (TKIs) and programmed cell death protein 1 (PD-1) inhibitors versus TACE combined with TKIs alone. Additionally, we explored prognostic factors, constructed a prognostic model, and validated it. METHODS: A retrospective analysis was conducted on 174 patients with unresectable hepatocellular carcinoma at Lu'an Hospital of Traditional Chinese Medicine Affiliated to Anhui University of Traditional Chinese Medicine from December 21, 2018, to January 15, 2023. Of these, 122 patients were treated with TACE + TKIs + PD-1, and 52 patients with TACE + TKIs. The objective was to compare overall survival (OS) and progression-free survival (PFS) between the two groups, analyze adverse events to assess the safety of the treatment regimen, explore risk factors affecting the prognosis of patients' OS and PFS, construct a prognostic model, and validate it through meta-analysis. RESULTS: The median OS in the TACE + TKIs + PD-1 group was significantly better than that in the TACE + TKIs group {20.8 months [95% confidence interval (CI): 13.6-28.0] CONCLUSIONS: The TACE + TKIs + PD-1 treatment regimen significantly outperformed TACE + TKIs in terms of OS, PFS, and DCR but increased the incidence of rash. An ECOG PS of 1 and BCLC-C stage were identified as risk factors for OS, while extrahepatic metastasis was an independent risk factor for PFS. The high accuracy of the survival prediction model constructed in this study provides a basis for clinical prognosis.