Purpose This study evaluated the effect of a nurse-led intervention program on compassion fatigue, burnout, compassion satisfaction, and psychological distress in nurses. Design and Methods A randomized controlled trial was conducted. A total of 48 clinical nurses were randomly allocated to intervention or control groups. The nurse-led intervention program was based on a cognitive-behavioral approach. The study outcomes were compassion fatigue, burnout, compassion satisfaction, and psychological distress. Findings It was determined that the psychological distress scores of the nurses participating in the program at the first follow-up were significantly lower than the control group. There was no significant difference between the groups in terms of compassion fatigue, burnout, and compassion satisfaction. Practical Implications To reduce the psychological distress of nurses, cognitive behavioral approach-based programs can be useful.