Background and Objectives <p>Given the substantial disease burden of unresectable hepatocellular carcinoma (uHCC) in China and the high costs associated with novel combination therapies, this study aims to evaluate, from the perspective of the Chinese healthcare system, the cost effectiveness of anlotinib combined with penpulimab versus sorafenib as first-line treatment for uHCC.</p> Methods <p>A partitioned survival model was developed using clinical data from the Phase III APOLLO trial. The model employed a 21-day cycle length and a 10-year time horizon. The incremental cost-effectiveness ratio (ICER) of anlotinib plus penpulimab versus sorafenib was calculated and compared against a predefined willingness-to-pay (WTP) threshold—set at three times China’s 2024 per capita GDP (40,354.27 US$ per quality-adjusted life year [QALY]) —to determine cost effectiveness. One-way and probabilistic sensitivity analyses were performed to assess the robustness of the model.</p> Results <p>Compared with the sorafenib group, the anlotinib plus penpulimab group incurred higher costs (44,068.90 US$ vs 38,142.25 US$) but provided greater survival benefits (1.20 QALYs vs 1.03 QALYs), yielding an ICER of 34,862.65 US$/QALY. One-way sensitivity analysis indicated that the utility value in the progressive disease state, the price of penpulimab, and utility value in the progression-free survival state had the most significant impact on the ICER. Probabilistic sensitivity analysis demonstrated robust results, with a 60.6% probability of anlotinib plus penpulimab being cost effective.</p> Conclusion <p>Our study suggests that anlotinib combined with penpulimab represents a cost-effective first-line treatment option for patients with uHCC from the perspective of the Chinese healthcare system. These results provide critical evidence to inform clinical practice and healthcare reimbursement policy.</p>