BACKGROUND: Chronic fatigue syndrome (CFS) is a chronic disease characterized by fatigue, complex symptoms and long duration. It incurs significant economic costs every year. Qigong Tuina therapy (QTT), a traditional Chinese therapy, is skilled in the treatment of fatigue. The objective of this study is to observe the effectiveness of QTT in treating patients with CFS. METHODS: A randomized controlled trial will recruit 128 patients with CFS. The patients will be allocated randomly in a 1:1 ratio to either the QTT group or the cognitive behavioral therapy (CBT) group. The interventions for both groups will be carried out once per week for 8 weeks. Then a 4 weeks follow-up will be conducted for all patients after the intervention. The primary outcome will be the changes in the Multidimensional Fatigue Inventory (MFI-20). Secondary outcomes will be measured by the 36-Item Short Form Health Survey (SF-36), Pittsburgh Sleep Quality Index (PSQI), Hospital Anxiety and Depression Scale (HADS), and functional magnetic resonance imaging (fMRI). The data will be analyzed at the baseline, 4 weeks into the intervention, at the end of the intervention, and 4 weeks after the intervention. The safety of interventions will be assessed after each treatment session. DISCUSSION: The trial aims to establish whether QTT is not inferior to CBT for CFS patients. This study provides vital information for an alternative and complementary therapy aimed at patients afflicted with CFS. ETHICS AND DISSEMINATION: Ethical approval was granted by Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine (2023SHL-KY-100-02). The findings will be disseminated through publications, conferences, and briefs to professional organizations. TRIAL REGISTRATION: ChiCTR2400081828, Chinese Clinical Trial Registry. Registered on March 13, 2024.