Ankle sprain is the most frequent sports-related musculoskeletal injury and a common cause of disability and lay-off time from sports. Chronic ankle instability (CAI) is a complex condition resulting from the interplay of a myriad of risk factors, which increase the risk of recurrent sprains. This chapter presents the full spectrum from an initial ankle sprain to the development of CAI, exploring the most common risk factors, underlying mechanisms, and diagnostic tools. Evidence-based stepwise rehabilitation and secondary prevention strategies play a crucial role in restoring ankle stability and mitigating functional impairments to reduce the risk of future subsequent sprains. Determining an athlete’s readiness for a safe and effective return to sports remains a clinical challenge. Future research should focus on objective assessment tools and individualized rehabilitation protocols to optimize the return to play decisions and long-term outcomes.