Research has demonstrated support for the efficacy of mindfulness-based stress reduction (MBSR) in alleviating psychological distress and symptoms. Less is known, however, about the mechanisms through which MBSR achieves its outcomes. This study examined mindfulness and self-compassion as potential mediators of MBSR’s effects on several processes and behaviors related to emotion regulation, using data from a randomized trial of MBSR versus waitlist (WL), in which MBSR participants demonstrated significantly greater improvements in worry, fear of emotion, difficulties in emotion regulation, suppression of anger, and aggressive anger expression. Mediation analysis using bootstrap resampling indicated that increases in self-compassion mediated MBSR’s effects on worry, controlling for change in mindfulness. Increases in mindfulness mediated the intervention’s effects on difficulties in emotion regulation, controlling for change in self-compassion. Both variables mediated MBSR’s effects on fear of emotion. These findings highlight the importance of mindfulness and self-compassion as key processes of change that underlie MBSR’s outcomes.