Objectives: The aim of this study was to evaluate the clinical effectiveness of craniosacral therapy (CST) in the management of any conditions. Methods: Two independent reviewers searched the PubMed, Physiotherapy Evidence Database, Cochrane Library, Web of Science, and Osteopathic Medicine Digital Library databases in August 2023, and extracted data from randomized controlled trials (RCT) evaluating the clinical effectiveness of CST. The PEDro scale and Cochrane Risk of Bias 2 tool were used to assess the potential risk of bias in the included studies. The certainty of the evidence of each outcome variable was determined using GRADEpro. Quantitative synthesis was carried out with RevMan 5.4 software using random effect models. Data synthesis: Fifteen RCTs were included in the qualitative and seven in the quantitative synthesis. For musculoskeletal disorders, the qualitative and quantitative synthesis suggested that CST produces no statistically significant or clinically relevant changes in pain and/or disability/impact in patients with headache disorders, neck pain, low back pain, pelvic girdle pain, or fibromyalgia. For non-musculoskeletal disorders, the qualitative and quantitative synthesis showed that CST was not effective for managing infant colic, preterm infants, cerebral palsy, or visual function deficits. Conclusions: The qualitative and quantitative synthesis of the evidence suggest that CST produces no benefits in any of the musculoskeletal or non-musculoskeletal conditions assessed. Two RCTs suggested statistically significant benefits of CST in children. However, both studies are seriously flawed, and their findings are thus likely to be false positive.