Background <p>Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with limited treatment success in advanced stages. Tyrosine kinase inhibitors (TKIs), such as sorafenib and lenvatinib, are the first-line treatments; however, their modest survival benefits and toxicity require better alternatives. Immune checkpoint inhibitors (ICIs) have shown promise; however, direct comparisons between ICI-based regimens and TKIs, particularly those stratified by hepatocellular carcinoma (HCC) etiology, are lacking.</p> Methods <p>We conducted a systematic review and meta-analysis following PRISMA guidelines, with a protocol registered in PROSPERO (CRD420251131652). We searched the PubMed, Embase (OVID), and CENTRAL databases to compare ICI-based regimens with TKI monotherapies for advanced or unresectable HCC. Randomized controlled trials and high-quality observational studies reporting clinical outcomes (overall survival [OS], progression-free survival [PFS], objective response rate [ORR], and disease control rate [DCR]) were included. Subgroup analyses were performed for HCC etiology (hepatitis B virus (HBV) infection, hepatitis C virus (HCV), and non-viral causes) and liver function status (Child–Turcotte–Pugh [CTP] A vs. B/C). Hazard ratios (HRs) and risk ratios (RRs) were pooled using a random-effects model.</p> Results <p>Seventeen studies (randomized controlled trials and observational studies) that included patients with advanced HCC were included. ICI-based regimens significantly improved overall survival (HR = 0.81; 95% confidence interval (CI): 0.68–0.95; <i>I</i>² = 78%) and progression-free survival (HR = 0.76; 95% CI: 0.64–0.91; <i>I</i>² = 83%) compared to that with TKIs. The objective response rate (RR = 1.59; 95% CI: 1.11–2.28) and the disease control rate (RR = 1.10; 95% CI: 1.01–1.21) were also better than that with TKIs. In terms of safety, ICIs showed a lower risk of adverse events of any grade and grades 3–4. Subgroup analyses revealed that ICIs provided significant survival benefit in HBV-related HCC (HR = 0.70; 95% CI: 0.60–0.82), while no statistically significant advantage was observed in HCV-related or non-viral HCC. Furthermore, ICI-based therapies conferred a survival benefit primarily in patients with preserved liver function (CTP A: OS HR = 0.82; 95% CI: 0.71–0.95; PFS HR = 0.76; 95% CI: 0.63–0.92), while patients with impaired liver function (CTP B/C) did not receive significant benefit.</p> Conclusions <p>ICI-based therapies are more effective and better tolerated than are TKI monotherapies for advanced HCC, particularly in patients with HBV-related disease and preserved liver function. The efficacy appears to be attenuated in HCV-related and non-viral HCC, as well as in patients with impaired liver function, underscoring the importance of considering both disease etiology and liver functional reserve in guiding systemic treatment strategies.</p>