Abstract Aim To evaluate the long‐term cost‐effectiveness of tirzepatide (5, 10 and 15 mg doses), a novel glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) receptor agonist, versus semaglutide 1.0 mg, an injectable glucagon‐like peptide‐1 receptor agonist, based on the results of the head‐to‐head SURPASS‐2 trial, from a US healthcare payer perspective. Materials and Methods The PRIME Type 2 Diabetes Model was used to make projections of clinical and cost outcomes over a 50‐year time horizon. Baseline cohort characteristics, treatment effects and adverse event rates were derived from the 40‐week SURPASS‐2 trial. Intensification to insulin therapy occurred when HbA1c reached 7.5%, in line with American Diabetes Association recommendations. Direct costs in 2021 US dollars (US$) and health state utilities were derived from published sources. Future costs and clinical benefits were discounted at 3% annually. Results All three doses of tirzepatide were associated with lower diabetes‐related complication rates, improved life expectancy, improved quality‐adjusted life expectancy and higher direct costs versus semaglutide. This resulted in incremental cost‐effectiveness ratios of US$ 75 803, 58 908 and 48 785 per quality‐adjusted life year gained for tirzepatide 5, 10 and 15 mg, respectively, versus semaglutide. Tirzepatide remained cost‐effective versus semaglutide over a range of sensitivity analyses. Conclusions Long‐term projections based on the SURPASS‐2 trial results indicate that 5, 10 and 15 mg doses of tirzepatide are likely to be cost‐effective versus semaglutide 1.0 mg for the treatment of type 2 diabetes in the United States.