Current research is intended to see the efficacy of the integration of spirituality and Cognitive Behavior Therapy (CBT) in reducing depression in patients with cardiac illnesses. The hypothesis under consideration is that there will be a significant differences in the level of depression experienced by patients with cardiac illnesses before and after the integrative treatment of spirituality and Cognitive Behavior Therapy (CBT). This study included (N =05) cardiac patients including females (n = 02) and males (n = 03) from a private hospital in Karachi, Pakistan. The age of patients ranged between 36-59 years (M = 49.00, SD = 9.62). Depression in Chronic Illnesses Scale (Yaseen, 2014) was used in the pre-and-post intervention stages to test the efficacy of the treatment applied. This study utilized a Twelve Sessions (1 session per week) manualized treatment approach that focuses on spiritual growth and decreasing depression through a Spiritually Informed Cognitive Behavioral Therapy (CBT; Good, 2010) for the treatment of depression in patients with cardiac illnesses. Results of the paired sample t-test revealed significantly large differences in pre-post assessment(r=3.82). Patients in post-test significantly exhibited lower level of depression as compared to the pre-test results. In conclusion, this study can provide guidelines to mental health practitioners to decrease or prevent depression among cardiac patients. Furthermore, awareness programs can be started to educate patients about depression at the very initial stages of diagnosis of medical illness.