Mindfulness-Based Stress Reduction is a secular behavioral medicine program that has roots in meditative spiritual practices. Thus, spirituality may partly explain Mindfulness-Based Stress Reduction outcomes. Participants (N = 279; M (SD) age = 45(12); 75% women) completed an online survey before and after an 8-week Mindfulness-Based Stress Reduction program. Structural equation modeling was used to test the hypothesis that, following Mindfulness-Based Stress Reduction, the relationship between enhanced mindfulness and improved health-related quality of life is mediated by increased daily spiritual experiences. Changes in both spirituality and mindfulness were significantly related to improvement in mental health. Although the initial mediation hypothesis was not supported, an alternate model suggested that enhanced mindfulness partly mediated the association between increased daily spiritual experiences and improved mental health-related quality of life (indirect effect: β = 0.07, P = 0.017). Effects on physical health-related quality of life were not significant. Findings suggest a novel mechanism by which increased daily spiritual experiences following Mindfulness-Based Stress Reduction may partially explain improved mental health as a function of greater mindfulness.