Objective This study aimed to evaluate the long-term cost-effectiveness of once-weekly subcutaneous semaglutide versus polyethylene glycol loxenatide (PEG-loxenatide) in patients with type 2 diabetes uncontrolled on metformin, from a Chinese healthcare systems perspective. Methods The study applied the Swedish Institute of Health Economics Diabetes Cohort Model to evaluate the long-term clinical and economic outcomes of once-weekly treatment of semaglutide at 0.5 mg and 1.0 mg, respectively, versus PEG-loxenatide 0.2 mg, over a 40-year time horizon. Baseline cohort characteristics were collected from the SUSTAIN China trial. A network meta-analysis was conducted to obtain comparative treatment effects of once-weekly semaglutide and PEG-loxenatide based on two phase 3a clinical trials. Drug costs were sourced from the national bidding price of China. Outcomes were discounted at 5.0% per annum. One-way sensitivity analysis and probabilistic sensitivity analysis were conducted to assess the uncertainty of the base-case results. Results When compared with PEG-loxenatide 0.2 mg, the projections of outcomes over the 40-year time horizon in patients with type 2 diabetes uncontrolled on metformin showed that treatment with once-weekly semaglutide 0.5 mg and 1.0 mg were associated with improved discounted life expectancy by 0.08 and 0.12 years, and improved discounted quality-adjusted life expectancy by 0.16 and 0.22 quality-adjusted life-years, respectively. Once-weekly semaglutide 0.5 mg and 1.0 mg were achieved at lifetime cost savings of 19,309 China Yuan (CNY) and 10,179 CNY, respectively. Sensitivity analyses verified the robustness of the results. Conclusion From the perspective of Chinese healthcare systems, treatment with once-weekly subcutaneous semaglutide represents a dominant option versus PEG-loxenatide for patients with type 2 diabetes uncontrolled on metformin.