Background: Stress-related, behavioral or chronic diseases require a holistic therapeutic approach. Mind-body medicine (MBM) uses the interaction between mind, body, behavior, and the environment to affect physical and psychological health and function. This integrative strategy can be applied in clinical settings, e.g., in an outpatient clinic, to improve well-being as well as clinical outcomes. We hypothesized an improvement of flourishing, mindfulness, sense of coherence, and quality of life through a comprehensive MBM program. In addition, we hypothesized correlations between the measures themselves as well as between the measures influenced by the intervention. Methods: We conducted a longitudinal cohort study in an outpatient clinic setting (n = 48 patients, with various diagnoses). A questionnaire battery, consisting of SF-12, Flourishing Scale (FS, FS-D), Freiburg Mindfulness Inventory (FMI), and Sense of Coherence Scale (SOC9), was used and applied in a pre-to-post format over a period of 18 weeks. The intervention was a 12-week MBM group program, with 1 session of 7 h per week. Results: The pre-post comparison of the measures showed significant improvements in psychological health, flourishing, mindfulness, and coherence. We were able to verify correlations between the measures themselves, apart from physical health. Coherence correlated with psychological health, influenced by the intervention. Further analyses showed associations between coherence, mindfulness, and flourishing. Conclusions: The MBM program improved measures of psychological health and decreased the level of suffering from chronic disease. MBM led to an improvement of disease coping and appraisal of individual ailments, thereby enhancing quality of life. Personal flourishing, coherence, and mindfulness seem to interact with each other.