ImportanceResearch shows that Tobacco 21 (T21) policies with a minimum legal access age for tobacco products of 21 years reduce smoking, yet their impact varies across US states due to differences in smoking behaviors, mortality rates, and policy coverage.ObjectiveTo quantify potential reductions in smoking-attributable mortality associated with Tobacco 21 policies for each of the 50 states and Washington, DC.Design, Setting, and ParticipantsThe Cancer Intervention Surveillance and Modeling Network (CISNET) Tobacco Control Policy Model of smoking was used with detailed state-specific data on smoking initiation, smoking cessation and mortality rates as they vary by age, gender, and birth cohort for 50 US states and the District of Columbia. This was integrated with comprehensive data on T21 policy coverage at the local and state levels from 2005 to 2024, and then T21 policy effects from quasi-experimental studies were applied to simulate each state’s experience of T21 policies, quantifying potential mortality reductions from 2005 to 2100.ExposuresCigarette smoking.Main Outcomes and MeasuresEstimated smoking-attributable deaths averted and life-years gained compared with a baseline scenario.ResultsEarly statewide T21 adoption in California, combined with its large population, was associated with more than 27 000 premature deaths averted through 2100, whereas statewide implementation in Kentucky was associated with 15 000 averted premature deaths. In Massachusetts, T21 policies were associated with 8000 averted premature deaths, largely attributed to municipal T21 policies covering most residents. Wisconsin—lacking state or local policies—requires enforcement of federal T21 to prevent up to 10 000 premature deaths. Across the country, comprehensive enforcement of federal, state, and local T21 laws were associated with up to 526 000 premature deaths averted and 13.3 million life-years gained by 2100. Enforcement of only state and local policies was associated with 442 000 premature deaths averted.Conclusions and RelevanceThis study found that early adoption and implementation of T21 policies maximizes potential premature mortality reductions. However, the strength of T21 policies and enforcement varies widely across states. Enforcement of the federal T21 law is critical in the 8 states without state-level T21 cigarette policies of their own.