OBJECTIVE: To conduct a systematic review with meta-analysis assessing the effectiveness of conservative rehabilitation programs for improving health-related quality of life (HRQL) in individuals with chronic ankle instability (CAI). DATA SOURCES: PubMed, MEDLINE, CINAHL, and SPORTDiscus were searched from inception to January 2016. STUDY SELECTION: Studies were included if the researchers examined the effects of a conservative rehabilitation protocol in individuals with CAI, used validated patient-reported outcomes (PROs) to quantify participant-perceived HRQL, and provided adequate data to calculate the effect sizes (ESs) and 95% confidence intervals (CIs). Studies were excluded if the authors evaluated surgical interventions, prophylactic taping, or bracing applications or examined only the immediate effects of 1 treatment session. DATA EXTRACTION: Two investigators independently assessed methodologic quality using the Physiotherapy Evidence Database (PEDro) Scale. Studies were considered low quality if fewer than 60% of the criteria were met. Level of evidence was assessed using the Strength of Recommendation Taxonomy. Preintervention and postintervention sample sizes, means, and standard deviations of PROs were extracted. DATA SYNTHESIS: A total of 15 studies provided 24 participant groups that were included in the analysis. Seven high-quality studies with a median PEDro score of 50% (range = 10%-80%) and a median level of evidence of 2 (range = 1-2) were identified. The magnitudes of preintervention to postintervention PRO differences were examined using bias-corrected Hedges g ESs. Random-effects meta-analysis was performed to synthesize PRO changes across all participant groups. Positive ES values indicated better PRO scores at postintervention than at preintervention. The α level was set at .05. Meta-analysis revealed a strong ES with a nonoverlapping 95% CI (ES = 1.20, CI = 0.80, 1.60; P < .001), indicating HRQL improved after conservative rehabilitation. CONCLUSIONS: Based on the quality of the evidence and the results of the meta-analysis, grade A evidence showed that conservative rehabilitation produces large improvements in HRQL for people with CAI.