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Interventional studies in the recent past have shown that an individual’s religious-spiritual (R/S) well-being helps in coping with chronic disease. In this quasi-experimental study, we performed two different interventions in 24 patients with systemic sclerosis, lupus erythematosus, and melanoma. One group of patients performed R/S exercises or attended a disease-specific lecture, and were compared to another group of patients who underwent no intervention. The R/S exercises produced a significant increase in Hope Transcendent (0.001) with the Multidimensional Inventory of Religious/Spiritual Well-Being compared to the lecture. Quality of life (QoL) improved significantly, specifically for the Mental Component Score of the Medical Outcomes Study 36-Item Short Form Health Survey, after the R/S exercises (p = 0.033) as well as the lecture (p = 0.011). This pilot study provided interesting insights on the impact of spiritual exercises in regard to Hope Transcendent, which was uniquely associated with the intervention. The study provided empirical evidence of the importance of the intervention, which would be valuable for the management of specific diseases in the clinical setting. This dimension of spirituality may help to overcome anxiety and fear of the inevitability of death while enabling patients to cope with chronic disease.