Objectives: Ozone (O) gas is being used for chronic pain relief in knee osteoarthritis (KOA). However, there are controversies whether this gas can be medically useful in KOA pain treatments. The aim of this study was to evaluate the effectiveness of intra-articular ozone therapy for pain relief in KOA subjects using a systematic review and meta-analysis and standardized mean difference (SMD) as the effect size. Method: Using specialized biomedical online databases of Pubmed Central, Pubmed, Medline, Google scholar, Scopus and Embase databases without the beginning date restriction until July 2018, the systematic review retrieved 10 studies for meta-analysis after fulfilling the inclusion and exclusion criteria.Results: Analysis of Q and I% indices showed a high heterogeneity in the selected studies (2600.330 and 99.654, respectively), thus, the random-effects model was chosen for SMD calculation. The primary analysis for the main hypothesis found that the weighted pooled effect size for the impact of intra-articular ozone therapy for pain reduction was as follows: SMD= -28.551 (95% confidence interval, -32.553 to -24.549). The P-value for the significance of the combined SMD examined by the z-test was 0.000 and thus, it was clearly considered statistically significant.Conclusion: This meta-analysis presents evidence that intra-articular ozone therapy is an effective way for chronic pain management in KOA.