ImportanceSmoking causes considerable noncommunicable diseases, perinatal morbidity, and mortality.ObjectiveTo investigate the associations of population-level tobacco-control policies with health outcomes.Data SourcesPubMed, EMBASE, Web of Science, Cumulated Index to Nursing and Allied Health Literature, and EconLit were searched from inception to March 2021 (updated on 1 March 2022). References were manually searched.Study SelectionStudies reporting on associations of population-level tobacco control policies with health-related outcomes were included. Data were analyzed from May to July 2022.Data Extraction and SynthesisData were extracted by 1 investigator and cross-checked by a second investigator. Analyses were conducted using the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline.Main Outcomes and MeasuresThe primary outcomes were respiratory system disease (RSD), cardiovascular disease (CVD), cancer, mortality, hospitalization, and health care utilization. The secondary outcomes were adverse birth outcomes, such as low birth weight and preterm birth. Random-effects meta-analysis was used to estimate pooled odds ratios (ORs) and 95% CIs.ResultsOf 4952 records identified, 144 population-level studies were included in the final analysis; 126 studies (87.5%) were of high or moderate quality. The most frequently reported policies were smoke-free legislation (126 studies), followed by tax or price increases (14 studies), multicomponent tobacco control programs (12 studies), and a minimum cigarette purchase age law (1 study). Smoke-free legislation was associated with decreased risk of all CVD events (OR, 0.90; 95% CI, 0.86-0.94), RSD events (OR, 0.83; 95% CI, 0.72-0.96), hospitalization due to CVD or RSD (OR, 0.91; 95% CI, 0.87-0.95), and adverse birth outcomes (OR, 0.94; 95% CI, 0.92-0.96). These associations persisted in all sensitivity and subgroup analyses, except for the country income category, for which a significant reduction was only observed in high-income countries. In meta-analysis, there was no clear association of tax or price increases with adverse health outcomes. However, for the narrative synthesis, all 8 studies reported statistically significant associations between tax increases and decreases in adverse health events.Conclusions and RelevanceIn this systematic review and meta-analysis, smoke-free legislation was associated with significant reductions in morbidity and mortality related to CVD, RSD, and perinatal outcomes. These findings support the need to accelerate the implementation of smoke-free laws to protect populations against smoking-related harm.