Lateral ankle sprains are the most common injuries sustained during physical activity. The epidemiologic trends associated with chronic ankle instability (CAI) suggest that current rehabilitation approaches may be inadequate. We sought to synthesize best-practices evidence for the rehabilitation of patients with acute ankle sprains and CAI through the integration of emerging paradigms in perception, the dynamics of skill acquisition, and the biopsychosocial model of function, disability, and health. From the best available evidence, 4 key factors emerged for effective treatment and rehabilitation strategies: pain reduction, external ankle support for up to 1 year, progressive return to motion, and coordination training. We combined these factors into a meta-theoretical framework that centers on the perceptual interdependence of the cellular, local, and global functioning levels by linking insights from the bodyself neuromatrix, the dynamics of skill acquisition, and the biopsychosocial model. Based on the best-practice recommendations from systematic reviews, ankle-sprain rehabilitation represents a multidimensional phenomenon governed by perception. The impairments, activity limitations, and participation restrictions associated with CAI may be linked to perceptualinterdependence alterations. Pain and edema reduction, the use of external ankle support for up to 1 year, progressive return to motion, and coordination training foster enhanced perceptual interdependence from cells to society. Using the perceptualinterdependence framework for ankle-sprain rehabilitation, we offer new insights for charting the course of effective strategies for enhancing function, reducing disability, and preventing the long-term sequelae associated with CAI.