BACKGROUND: Chronic widespread pain (CWP) is a core symptom of fibromyalgia that is associated with significant morbidity and mortality. Despite the widespread recommendation for physical activity (PA) in management, the heterogeneity of PA prescriptions limits the in-depth evaluation of its efficacy. By triangulating clinical interventional evidence with human genetic evidence, the aim of this study was to investigate the role of influencing factors such as PA mode, course of treatment, and intensity on PA in the prevention and treatment of CWP. METHODS: Ten international and regional databases were searched for articles published between January 2014 and July 2024. Randomized control trials with CWP or fibromyalgia as an entry criterion and PA as an intervention were included. Meta-analyses were performed using fixed- or random-effects models based on heterogeneity, and subgroup analyses were conducted. Mendelian randomization (MR) was used to estimate the effects of the genetic variants linked to PA intensity on CWP risk. RESULTS: The analysis included 11 studies with 540 participants. PA effectively improved pain perception (MD: -1.47
95% CI: -2.23, -0.72), depression (MD: -4.77
95% CI: -7.40, -2.14), and overall quality of life (SMD: -1.43
95% CI: -2.16, -0.69). MR analysis revealed that several PA intensities were associated with reduced susceptibility to CWP: walking for pleasure (OR: 0.950
95% CI: 0.934-0.966), light do-it-yourself (DIY) (OR: 0.976
95% CI: 0.961-0.992), strenuous sports (OR: 0.923
95% CI: 0.880-0.967), and other exercises (OR: 0.957
95% CI: 0.942-0.973). CONCLUSION: PA interventions are beneficial for reducing pain perception and mood disorders and enhancing the quality of life of patients with CWP. A treatment course of approximately three months is preferable, with Ba-Duan-Jin potentially more effective than other PAs, and high-intensity PA offers the most significant protective effect against CWP.