INTRODUCTION: This study aimed to evaluate the cost-effectiveness of donafenib compared to sorafenib and lenvatinib as first-line treatments for patients with advanced hepatocellular carcinoma (HCC) in China. METHODS: A partitioned survival model was developed to estimate the clinical and economic outcomes of donafenib, sorafenib, and lenvatinib for advanced HCC. The key clinical data of these targeted therapies were assessed through a network meta-analysis. The cost and health utilities were mainly collected from the literature. Quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios (ICER) were the primary outcomes. Model uncertainty was tested with one-way sensitivity analyses, scenario analyses, and probabilistic sensitivity analyses (PSA). RESULTS: For health outcomes, donafenib gained the highest QALYs among the three treatments, followed by lenvatinib and sorafenib (1.106, 0.999, and 0.915 QALYs, respectively). For cost, donafenib was the cheapest option, followed by sorafenib and lenvatinib ($42,116, $43,193, and $44,261). The PSA indicated that the probability of being cost-effective for donafenib was 86.98% and 93.56% when the willingness-to-pay thresholds were one and three times the gross domestic product per capita in China, respectively. The one-way sensitivity analyses and scenario analyses also found the results to be robust. CONCLUSION: Compared to sorafenib and lenvatinib, donafenib was likely to be a cost-effective treatment with the highest QALYs and the lowest cost for patients with advanced HCC in China.