ImportanceMortality from cardiovascular disease (CVD) varies across communities and is associated with known structural and population health factors. Still, a population’s well-being, including sense of purpose, social relationships, financial security, and relationship to community, may be an important target to improve cardiovascular health.ObjectiveTo examine the association of population level measures of well-being with rates of CVD mortality in the US.Design, Setting, and ParticipantsThis cross-sectional study linked data from the Gallup National Health and Well-Being Index (WBI) survey to county-level rates of CVD mortality from the Centers for Disease Control and Prevention Atlas of Heart Disease and Stroke. Participants were respondents of the WBI survey, which was conducted by Gallup with randomly selected adults aged 18 years or older from 2015 to 2017. Data were analyzed from August 2022 to May 2023.Main Outcomes and MeasuresThe primary outcome was the county-level rate of total CVD mortality; secondary outcomes were mortality rates for stroke, heart failure, coronary heart disease, acute myocardial infarction, and total heart disease. The association of population well-being (measured using a modified version of the WBI) with CVD mortality was assessed, and an analysis of whether the association was modified by county structural factors (Area Deprivation Index [ADI], income inequality, and urbanicity) and population health factors (percentages of the adult population who had hypertension, diabetes, or obesity; were currently smoking; and were physically inactive) was conducted. Population WBI and its ability to mediate the association of structural factors associated with CVD using structural equation models was also assessed.ResultsWell-being surveys were completed by 514 971 individuals (mean [SD] age 54.0 [19.2] years; 251 691 [48.9%] women; 379 521 [76.0%] White respondents) living in 3228 counties. Mortality rates for CVD decreased from a mean of 499.7 (range, 174.2-974.7) deaths per 100 000 persons in counties with the lowest quintile of population well-being to 438.6 (range, 110.1-850.4) deaths per 100 000 persons in counties with the highest quintile of population well-being. Secondary outcomes showed similar patterns. In the unadjusted model, the effect size (SE) of WBI on CVD mortality was −15.5 (1.5; P < .001), or a decrease of 15 deaths per 100 000 persons for each 1-point increase of population well-being. After adjusting for structural factors and structural plus population health factors, the association was attenuated but still significant, with an effect size (SE) of −7.3 (1.6; P < .001); for each 1-point increase in well-being, the total cardiovascular death rate decreased by 7.3 deaths per 100 000 persons. Secondary outcomes showed similar patterns, with mortality due to coronary heart disease and heart failure being significant in fully adjusted models. In mediation analyses, associations of income inequality and ADI with CVD mortality were all partly mediated by the modified population WBI.Conclusions and RelevanceIn this cross-sectional study assessing the association of well-being and cardiovascular outcomes, higher well-being, a measurable, modifiable, and meaningful outcome, was associated with lower CVD mortality, even after controlling for structural and cardiovascular-related population health factors, indicating that well-being may be a focus for advancing cardiovascular health.