Caregivers of people with mental illness are at increased risk of developing depression, anxiety, and stress. To investigate the effect of a compassion cultivation training (CCT) program on decreasing caregiver psychological distress. This waitlist-controlled randomized clinical trial was conducted in 2 different community settings in Denmark. Caregivers were excluded if they had a diagnosed and untreated mental illness, addiction, meditation practice, or current psychotherapeutic treatment. Enrollment occurred between May 2018 and March 2019. A repeated measurement model was used to examine the impact of the intervention. The primary analysis was based on the intention-to-treat principle. Data analysis was conducted from June 4 to July 7, 2020. Participants were randomized 1-to-1 to an 8-week CCT course or waitlist control. Block randomization was used with 40 participants in each block. The main outcome was reduction in psychological distress, as measured by the Depression, Anxiety, Stress Scale (DASS). Baseline, postintervention, and 3- and 6-month follow-up measurements were collected. Among 192 participants assessed for eligibility, 161 participants were included in the study (mean [SD] age, 52.6 [12.5] years; 142 [88.2%] women), with 79 participants randomized to the CCT intervention and 82 participants in the waitlist control group. At baseline, the mean (SD) DASS scores for the intervention vs control groups were 10.89 (8.66) vs 10.80 (8.38) for depression, 6.89 (6.48) vs 6.68 (5.33) for anxiety, and 14.96 (7.90) vs 15.77 (7.40) for stress. The CCT group experienced statistically significant improvement in the primary outcome in mean change from baseline vs the control group at postintervention (adjusted mean difference: depression, -4.16 [95% CI, -6.75 to -1.58]; P = .002; anxiety, -2.24 [95% CI, -3.99 to -0.48]; P = .01; stress, -4.20 [95% CI, -6.73 to -1.67]; P = .001), the 3-month follow-up (adjusted mean difference: depression, -3.78 [95% CI, -6.40 to -1.17]; P = .005; anxiety, -2.50 [95% CI, -4.27 to -0.73]; P = .006; stress, -3.76 [95% CI, -6.32 to -1.21]; P = .004), and the 6-month follow-up (adjusted mean difference: depression: -4.24 [95% CI, -6.97 to -1.52]; P = .002; anxiety, -2.12 [95% CI, -3.96 to -0.29]; P = .02; stress: -3.79 [95% CI, -6.44 to -1.13]; P = .005). These findings suggest that CCT was superior to the waitlist control in supporting caregivers' mental health. Statistically and clinically significant reductions in psychological distress were found and sustained at the 6-month follow-up. The improvements noted in this randomized clinical trial could serve to encourage implementation of future evidence-based programs for caregivers. ClinicalTrials.gov Identifier: NCT03730155.