Objective: To investigate the effectiveness of Anti-Inflammatory Drugs in the treatment of delayed onset muscle soreness (DOMS). Design: A systematic review and meta-analysis of randomized controlled clinical trials (RCTs). Setting: The PubMed/MEDLINE, EMBASE, SPORTDiscus, Scielo and CENTRAL databases were searched up until August 3, 2020. Studies that included 1) used an RCT design; 2) evaluated the effectiveness of anti-inflammatory drugs (NSAIDs) in treating DOMS; and 3) drugs should have been applied after exercise. Participants: Healthy participants who were free of acute or chronic diseases. There were no restrictions regarding the participants’ age, sex, level of activity. Interventions: Anti-Inflammatory Drugs (NSAIDs). Main Outcome Measures: Improvement of late muscle pain. Results: In total, 26 studies (n = 934 participants) were eligible for inclusion. The results of the meta-analysis fail to show superiority between the use and non-use of NSAIDs in the improvement of late muscle pain, as statistically significant differences were not verified (21 studies; standard mean difference (SMD)= 0.02; 95% confidence interval (CI) -0.58, 0.63; p=0.94; I2=93%). The quality of the synthesized evidence was very low according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria, and there was significant heterogeneity among the included studies. Conclusion: Use of NSAIDs in the management of DOMS does not appear to be superior to a control condition and/or placebo. However, these interpretations should be analysed with caution since the type of NSAID, dose/response relationship and volume/intensity of the effort made to induce different kinds of muscle damage varied across studies.