Background Prevention of cardiovascular disease (CVD) is a public health priority. The combination of physical activity, a healthy diet, and abstaining from tobacco plays an important role in prevention whereas aspects of psychosocial well‐being have largely been examined separately with conflicting results. This study evaluated whether the combination of indices of psychosocial well‐being was associated with less progression of coronary artery calcium (CAC). Methods and Results Participants were 312 women (mean age 50.8) from the SWAN (Study of Women’s Health Across the Nation) ancillary Heart Study, free of clinical CVD at baseline. A composite psychosocial well‐being score was created from 6 validated psychosocial questionnaires assessing optimism, vitality, life engagement, life satisfaction, rewarding multiple roles, and positive affect. Subclinical CAC progression was defined as an increase of ≥10 Agatston units over 2.3 years measured using electron beam tomography. Relative risk (RR) regression models examined the effect of well‐being on CAC progression, progressively adjusting for sociodemographic factors, depression, healthy lifestyle behaviors, and standard CVD risk factors. At baseline, 42.9% had a CAC score >0, and progression was observed in 17.6%. Well‐being was associated with less progression (RR, 0.909; 95% CI, 0.843−0.979; P =0.012), which remained significant with adjustment for potential confounders, depression, and health behaviors. Further adjustment for standard CVD risk factors weakened the association for the total sample (RR, 0.943; 95% CI, 0.871−1.020; P =0.142) but remained significant for the 134 women with baseline CAC>0 (RR, 0.921; 95% CI, 0.852−0.995; P =0.037). Conclusions Optimum early prevention of CVD in women may result from including the mind side of the mind‐heart‐body continuum.