Background: There is a paucity of research on mediators of change, within compassion training programs. The aim was to investigate the mediators, of an 8-week compassion cultivation training (CCT) program, on the effect of psychological distress on caregivers of people with a mental illness.Method: Longitudinal path models in a randomized controlled trial (RCT). One hundred ninety-two participants were assessed for eligibility, and 161 participants were included into the trial and randomized. The main outcome was psychological distress measured by the Depression, Anxiety and Stress scale at 6 months. Mediators included self-compassion (SC), mindfulness (FM), emotion regulation (ER), emotion suppression (ES), and cognitive reappraisal (CR). Baseline, post, and 3- and 6-month follow-up measurements were collected.Results: The mediated effects for CCT are as follows: depression at 6 months: SC: −1.81 (95% CI: −3.31 to −0.31); FM: −1.98 (95% CI: −3.65 to −0.33); ER: −0.14 (95% CI: −1.31 to 1.02); anxiety at 6 months: SC: −0.71 (95% CI: −1.82 to 0.40); FM: −1.24 (95% CI: −2.39 to −0.09); ER: 0.18 (95% CI: −1.04 to 1.40); stress at 6 months: SC: −1.44 (95% CI: −2.84 to −0.05); FM: −2.17 (95% CI: −3.63 to −0.71); ER: −0.27 (95% CI: −1.51 to 0.98).Conclusion: Mindfulness and self-compassion are important components in reducing psychological distress experienced by informal caregivers of people with a mental illness. Results contribute to the knowledge about the underlying mechanisms of CCT.