AbstractFatigue is barrier of physical activity participation in adults with chronic conditions. However, physical activity alleviates fatigue symptoms. This systematic review and meta-analysis aimed to (1) synthesise evidence from randomised controlled trials (RCTs) exploring the effects of physical activity interventions on fatigue reduction and (2) evaluate their effectiveness. Medline/CINAHL/EMBASE/Web of Science and Scopus were searched up to June 24th, 2023. Two reviewers independently conducted study screening and selection (RCTs), extracted data and assessed risk of bias (RoB2). Outcome was the standardised mean difference (SMD) with 95% confidence intervals in fatigue between experimental and control groups. 38 articles met the inclusion criteria. Overall, physical activity interventions moderately reduced fatigue (SMD = 0.54, p < 0.0001). Interventions lasting 2–6 weeks demonstrated a larger effect on fatigue reduction (SMD = 0.86, p < 0.00001). Interventions with 18–24 sessions showed a large effect on fatigue reduction (SMD = 0.97, p < 0.00001). Aerobic cycling and combination training interventions had a large to moderate effect (SMD = 0.66, p = 0.0005; SMD = 0.60, p = 0.0010, respectively). No long-term effects were found during follow-up. Physical activity interventions moderately reduced fatigue among adults with chronic conditions. Duration, total sessions, and mode of physical activity were identified as key factors in intervention effectiveness. Further research is needed to explore the impact of physical activity interventions on fatigue.