Background: Psychological distress is highly noticeable among caregivers working in residential youth care (RYC). Maintaining and enhancing caregivers' professional mental health and quality of life is crucial to achieve effective outcomes in RYC. Nevertheless, trainings to protect caregivers' mental health are scarce. Considering the buffering effect over negative psychological outcomes, compassion training could be beneficial in RYC. Objective: This study is part of a Cluster Randomized Trial examining the effects of the Compassionate Mind Training for Caregivers (CMT-Care Homes), looking at professional quality of life and mental health of caregivers working in RYC. Method: The sample was composed of 127 professional caregivers from 12 Portuguese residential care homes (RCH). RCHs were randomly allocated at experimental (N = 6) and control group (N = 6). Participants were assessed at baseline, post-treatment, and 3 and 6-month follow-ups, answering to the Professional Quality of Life Scale and the Depression, Anxiety and Stress Scale. Program effects were tested using a two-factor mixed MANCOVA, with self-critical attitude and education degree as covariates. Results: MANCOVA showed a significant Time × Group interaction effects (F = 1.890, p = 0.014; [eta-squared][subscript p] = 0.050), with CMT-Care Homes participants presenting lower scores on burnout, anxiety, and depression at 3 and 6-months follow-ups, when compared with controls. Participants that received CMT-Care Homes considered the program useful to deal with pandemic threats and with youth during lockdowns. Conclusions: This study shows the benefits of the CMT-Care Homes in helping professional caregivers reducing burnout, anxiety and depression, and dealing with pandemic challenges in RYC. Trial registration: This cluster randomized trial was registered at ClinicalTrials.gov (TRN: NCT04512092) on 6th August 2020.