Background/Objectives: Compassion Fatigue (CF) is a critical issue among healthcare professionals, exacerbated by exposure to trauma and chronic workplace stress. This pilot study evaluates the effectiveness of a Mindfulness-Oriented Professional Resilience (MOPR) program, a structured intervention designed to mitigate CF and enhance resilience in healthcare professionals. The program integrates mindfulness practices, arousal modulation techniques, and resilience-building strategies over six weekly sessions. Methods A sample of 73 healthcare workers (mean age 48.6, SD = 9.42) participated in the study, and pre–post data were analyzed using repeated measures ANOVA. Results: Results indicated significant improvements in professional quality of life, with increased Compassion Satisfaction (p < 0.001) and reductions in Burnout (p = 0.003) and Secondary Traumatic Stress (p < 0.001). Mindfulness skills improved significantly across four dimensions—Observing, Describing, Acting with Awareness, and Non-reactivity—with p-values ranging from <0.01 to <0.001. Arousal modulation showed increased Optimal Arousal Zone scores (p < 0.001) and reduced maladaptive stress responses, including Fight/Flight, Freeze, and Feigned Death (p < 0.05). Psychological well-being improvements were observed, particularly in Self-Acceptance (p = 0.014) and Positive Relations (p = 0.041). Conclusions: These findings suggest that the MOPR program is a promising intervention for healthcare professionals, supporting resilience and reducing the psychological burden of caregiving. Future controlled studies should explore its long-term efficacy in diverse clinical settings and in larger samples.