Psychological well-being is a good predictor of several health outcomes in cardiovascular disease patients (adherence, quality of life, and healthy behaviors). The perception of health control and a positive orientation seem to have a beneficial effect on health and well-being. Therefore, the aim of this study was to investigate the role of the health locus of control and positivity in the psychological well-being and quality of life of cardiovascular patients. A total of 593 cardiac outpatients completed the Multidimensional Health Locus of Control Scale, the Positivity Scale and the Hospital Anxiety and Depression Scale at baseline (January 2017) and 9 m later (follow-up;n= 323). A Spearman rank correlation coefficient and a structural equation modeling approach were determined to explore the relationships between those variables both cross-sectionally and longitudinally. A cross-sectional correlation analysis at baseline revealed that the internal health locus of control and positivity were negatively associated with anxiety (rs= −0.15 and −0.44,ps < 0.01) and depression (rs= −0.22 and −0.55,ps < 0.01) and positively associated with health-related quality of life (rs= 0.16 and 0.46,ps < 0.01). Similar outcomes were found at follow-up and in longitudinal correlations. According to the path analysis, positivity was found to be negatively associated with anxiety and depression level at baseline (β = −0.42 and −0.45,ps < 0.001). Longitudinally, positivity was negatively associated with depression (β = 0.15,p< 0.01) and together with the internal health locus of control, was positively associated with health-related quality of life (β = 0.16 and 0.10, respectively,ps < 0.05). These findings suggest that focusing on the health locus of control and especially positivity may be crucial in enhancing the psychological well-being of patients in the context of cardiac care. The potential impact of these results on future interventions is discussed.