INTRODUCTION: Standard treatments for intermediate-stage hepatocellular carcinoma (HCC), such as transarterial chemoembolization (TACE), offer limited efficacy, necessitating the exploration of additional therapeutic strategies. Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have shown potential to enhance HCC outcomes when combined with TACE. This meta-analysis aimed to evaluate safety and efficacy of TACE, TKIs, and ICIs (TACE + T + I) combination compared to TACE with TKIs alone (TACE + T) in patients with HCC. METHODS: A systematic search was performed in "PubMed," "Google Scholar," "Cochrane Library," "Web of Science," "Scopus," and "Embase" databases on November 1, 2024. Studies involving patients with HCC comparing TACE + T + I versus TACE + T were included. Efficacy outcomes including objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and adverse events were extracted. Meta-analysis was conducted using RevMan 5.4. RESULTS: Seventeen studies were included for analysis. Pooled analysis showed a marked improvement in ORR (risk ratio [RR] = 1.57, 95% CI: 1.36-1.80, p < 0.00001) and DCR (RR = 1.13, 95% CI: 1.06-1.20, p = 0.0004) for TACE + T + I regimen over TACE + T. TACE + T + I group also showed a marked benefit in OS (hazard ratio [HR] = 0.37, 95% CI: 0.29-0.48, p < 0.0001) and PFS (HR = 0.44, 95% CI: 0.36-0.53, p < 0.0001). No differences in adverse events were detected between the two groups, indicating comparable tolerability. CONCLUSION: The findings suggest that the addition of ICIs to TACE and TKI therapy offers substantial efficacy benefits without increasing toxicity for HCC patients. This combination therapy shows potential to improve DCR, ORR, PFS, and OS, underscoring the value of immunotherapy in enhancing outcomes in HCC. However, further randomized trials with standardized treatment protocols are needed to confirm these results and inform clinical guidelines.