Objectives: The primary purpose of the current study was to assess the effects of a mindfulness-based stress reduction (MBSR) program, facilitated by non-psychologist clinicians, for improving psychosocial well-being. A secondary purpose of the current study was to explore the role of self-compassion as a potential underlying factor for improvements in emotional distress. Application of these findings to a physical therapy setting is provided. Methods: One hundred and thirty participants with a variety of medical complaints completed an eight-week MBSR program at Vanderbilt University’s Osher Center for Integrative Medicine. Prior to the intervention and at the eight-week time point, participants completed measures for emotional distress (Brief Symptom Inventory), stress (Perceived Stress Scale-10), mindfulness (Mindfulness Attention and Awareness Scale), and self-compassion (Self-Compassion Scale). Wilcoxon signed-rank test was used to evaluate changes in outcomes after MBSR. Linear model estimation using ordinary least squares was used to evaluate the association between changes in self-compassion with changes in emotional distress. Results: Following MBSR, participants reported significant reductions in emotional distress (p < 0.001). Additionally, participants reported improvements in mindfulness and self-compassion (p < 0.001). Linear regression model revealed that changes in self-compassion were significantly associated with changes in emotional distress (p < 0.001). Discussion: An MBSR program conducted by non-psychologist clinicians was associated with improvements in emotional distress, stress, and self-compassion. MBSR is a promising adjunct intervention in which principles can be integrated within a physical therapy approach for chronic conditions. Level of Evidence: 3B