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Abstract Introduction: Occupational Therapy (OT) emphasizes meaningful engagement in goal-directed and fulfilling activities to promote well-being. The Flow State, a psychological state of deep immersion, aligns with OT principles and has been studied in various patient populations. However, no research has explored the connection between Flow Theory and OT approach to fatigue management. Fatigue significantly impacts daily life, making OT interventions crucial. This study hypothesizes a possible enhancer role of Flow State in OT addressed to people who experience fatigue, improving their energy management and quality of life (QOL). Objectives: this study aims to assess the effectiveness of an OT intervention focused on Flow achievement for individuals with fatigue related to Chronic Fatigue Syndrome (CFS), Cancer and Multiple Sclerosis (MS). The primary outcome measure is Flow experience, with fatigue level, occupational balance and subjective QOL as secondary outcomes. Methods: a single-blind randomized controlled trial (RCT) will compare standard OT with an experimental OT approach incorporating Flow principles. Participants, recruited according to inclusion and exclusion criteria, will be randomly assigned by blocked randomization to either group, with interventions spanning 8–12 weeks. The experimental group will experience challenge-skill balance adjustments, Mindfulness and the Dynamic Occupation in Time (DOiT) model to enhance Flow. Primary and secondary outcomes will be measured pre- and post-intervention. Practice Implications: if successful, this intervention could offer a novel OT approach to fatigue management, integrating Flow strategies to optimize occupational performance, reduce drugs assumption and promote well-being. Conclusion: this study seeks to fill a gap in OT literature, providing new research opportunities and proposing Flow State as a potential enhancer for OT interventions focused on fatigue management.