Despite the growing evidence linking faith with health and well-being, national leaders noted the need to explore the mechanism underlying these linkages. The goal of this prospective study was to investigate the psychosocial mechanisms involved in the preoperative use of private prayer for coping and the effects of such act on short-term quality of life (SPQOL) in 294 patients following open-heart surgery. Using established instruments, three interviews were conducted with middle-aged and older patients (average age 62) at two weeks and two days preoperatively, then 36 days postoperatively. The endpoints were assessed with levels of distress (e.g., depression and anxiety) and fatigue symptoms. Structural equation modeling was used to test a theoretical model. The final model showed the indirect influence of using prayer for coping on SPQOL through the mediation of cognitive coping and perceived social support. However, this mediation was not observed for behavioral, anger, and avoidant coping. Psychosocial factors may explain the potential role of using prayer for coping on short-term postoperative quality of life.