Importance Newer antiobesity medications lead to greater weight loss and lower cardiometabolic risks. However, the high costs of these medications have raised policy questions about their value and coverage decisions. Objective To compare the cost-effectiveness of 4 antiobesity medications with lifestyle modification vs lifestyle modification alone in the US. Design, Setting, and Participants A lifetime cost-effectiveness analysis was conducted in 2024 using the validated Diabetes, Obesity, Cardiovascular Disease Microsimulation model for US adults. Data were included from the 2017-2020 National Health and Nutrition Examination Survey of 4823 individuals (representing 126 million eligible US adults) aged 20 to 79 years who would meet clinical trial inclusion criteria for antiobesity medications. Individual-level simulations projected long-term cardiometabolic outcomes, quality-adjusted life-years (QALYs), and health care expenditures. Probabilistic sensitivity analyses, subgroup analyses (across body mass index [BMI] categories [≥30 or ≥27 and at least 1 weight-related comorbidity], presence of comorbidities), and multiple scenario analyses (varying treatment discontinuation rates, value-based pricing benchmarks) were conducted. Future costs and QALYs were discounted at 3% annually. Interventions Lifestyle modification with naltrexone-bupropion, phentermine-topiramate, semaglutide, or tirzepatide vs lifestyle modification alone. Main Outcomes and Measures Obesity, diabetes, and cardiovascular disease cases averted, life-years and QALYs gained, costs incurred (2023 US dollars), and incremental cost-effectiveness ratios. Results Among the 126 million eligible US adults, the mean age was 48 (SE, 0.5) years; 51% were female; and the initial mean BMI was 34.7 (SE, 0.2); and 85% had at least 1 weight-related comorbidity. Over a lifetime, tirzepatide would avert 45 609 obesity cases (95% uncertainty interval [UI], 45 092-46 126) per 100 000 individuals and semaglutide would avert 32 087 cases (95% UI, 31 292-32 882) per 100 000 individuals. Tirzepatide would reduce 20 854 incident cases of diabetes (95% UI, 19 432-22 276) per 100 000 individuals and semaglutide would reduce 19 211 cases (95% UI, 17 878-20 544) per 100 000 individuals. Tirzepatide would reduce 10 655 cardiovascular disease cases (95% UI, 10 124-11 186) per 100 000 individuals and semaglutide would reduce 8263 cases (95% UI, 7738-8788) per 100 000 individuals. Despite the largest incremental QALY gains of 0.35 for tirzepatide and 0.25 for semaglutide among all antiobesity medications, the incremental cost-effectiveness ratios were $197 023/QALY and 467 676/QALY, respectively. To reach the$100 000/QALY threshold, their prices would require additional discounts by 30.5% for tirzepatide and 81.9% for semaglutide from their current net prices. Naltrexone-bupropion was cost saving due to its lower cost and had an 89.1% probability of being cost-effective at $100 000/QALY, whereas phentermine-topiramate had a 23.5% probability of being cost-effective at$100 000/QALY. Tirzepatide and semaglutide both had a 0% probability across all QALY threshold ranges examined ($100 000-$200 000/QALY). Conclusions and Relevance This economic evaluation found that although tirzepatide and semaglutide offered substantial long-term health benefits, they were not cost-effective at current net prices. Efforts to reduce the net prices of new antiobesity medications are essential to ensure equitable access to highly effective antiobesity medications.