BACKGROUND: Chronic ankle instability (CAI) is a common and highly disabling condition. Although several studies have evaluated and analyzed prevention and treatment strategies for CAI, an unbiased and systematic synthesis of evidence is required to provide the most powerful and comprehensive evidence-based measures for the its prevention and treatment of CAI. This study aimed to synthesize evidence from the existing literature addressing the treatment and prevention of CAI. METHODS: The PubMed, Embase, Cochrane, and Web of Science databases were systematically searched for relevant studies from inception to December 12, 2023. Data on effect sizes and corresponding 95 % confidence intervals for selected intervention measures were extracted. Systematic reviews were assessed for quality of included studies using a measurement tool (i.e., "AMSTAR 2"). RESULTS: In total, 37 studies were included, among which 21 (57 %) were of high or moderate quality. Strong evidence suggested that lower weight (P < 0.001), lower body mass index (P = 0.002), and non-stability defects (P = 0.04) significantly reduced the risk of developing CAI. Strong evidence supported exercise and moderate evidence supported manual therapy, acupuncture, and surgery for improving CAI. Additionally, external support plays an active role in the treatment process of CAI. CONCLUSION: This is the first study synthesizing evidence supporting interventions for the treatment and prevention of CAI. Low body weight and body mass index were effective preventive measures against CAI. Exercise, manual therapy, acupuncture, and surgery can improve ankle function in patients with CAI. Plantar sensory treatment and neuromuscular training may be good therapeutic options for patients with CAI. LEVEL OF EVIDENCE: Level I.