ImportanceAlthough many people report a desire to quit smoking, concerns about mental health worsening after quitting are often raised by clinicians and people who smoke.ObjectiveTo assess changes in mental health following smoking cessation using 3 confirmatory coprimary analytical approaches.Design, Setting, and ParticipantsThis cohort study was conducted using data from a large, randomized clinical trial, the Evaluating Adverse Events in a Global Smoking Cessation Study. Analytical approaches included multivariable Tobit regression, propensity score adjustment, and instrumental variable regressions conducted from August to October 2022. Missing data were imputed for sensitivity analysis. The trial occurred in 16 countries at 140 centers between 2011 and 2015. Only data from participants who completed the trial collected in the US were available for this secondary analysis. Participants included adults with or without a psychiatric disorder who smoked.ExposureSmoking abstinence between weeks 9 through 24.Main Outcomes and MeasuresAnxiety and depression scores were measured using the Hospital Anxiety and Depression Scale at 24 weeks, where a lower score indicates better mental health (range, 0-21).ResultsOf the 4260 participants included (mean [SD] age, 46.5 [12.4] years; 2485 women [58.3%]; 3044 White individuals [71.5%]), 2359 (55.4%) had a history of mental illness. The mean (SD) baseline Hospital Anxiety and Depression Scale score was 4.25 (3.68) (median [IQR], 3 [1-6]) for anxiety and 2.44 (2.91) (median [IQR], 1 [0-4]) for depression. After adjustment for demographics and baseline variables, smoking cessation was associated with a decrease in scores for both anxiety (−0.40 point; 95% CI, −0.58 to −0.22 point) and depression (−0.47 point; 95% CI, −0.61 to −0.33 point) compared with continuing smoking. Similarly, propensity score–adjusted models indicated that smoking cessation was associated with reduced scores for anxiety (β = −0.32; 95% CI, −0.53 to −0.11) and depression (β = −0.42; 95% CI, −0.60 to −0.24). Instrumental variable analysis was underpowered, and estimates were imprecise. Findings were robust to planned sensitivity and subgroup analyses, with larger effect sizes in people with a history of mental illness.Conclusions and RelevanceIn this cohort study of people with and without psychiatric disorders, smoking cessation, sustained for at least 15 weeks, was associated with improved mental health outcomes in observational analyses, but the instrumental variable analysis provided inconclusive evidence. Findings like these may reassure people who smoke and their clinicians that smoking cessation likely will not worsen and may improve mental health.