Numerous studies have found mindfulness-based stress reduction (MBSR) to be useful for a range of problems including anxiety, pain, and coping with a medical illness. As the field matures, there is a growing interest in mediational factors associated with the beneficial effects of MBSR. Self-compassion is a construct of increasing focus in empirical study and may play a role in the change process leading to improvement in well-being through MBSR. The primary goal of this pilot study was to examine the role of self-compassion in producing improved well-being following an 8-week MBSR program with a community-based sample. Participants engaged in a MBSR program at a major academic medical center and completed the Profile of Mood States (POMS), Mindful Attention Awareness Scale (MAAS), and the Self-Compassion Scale (SCS) pre- and post-MBSR course. Results demonstrated significant reduction of symptoms on the POMS and significant increases on the MAAS and SCS at the end of the program, indicating notable improvements in well-being. Mediation analyses demonstrated that changes in self-compassion mediated the relationship between mindfulness and well-being following MBSR training (serial indirect effects; β = − 9.45, CI (− 39.06, − 7.50)). These results suggest that mindfulness may provide a pathway to cultivating self-compassion in MBSR, which may be associated with enhanced well-being.