Background: Fluoxetine is a serotonin-specific reuptake inhibitor antidepressant and is the only approved pharmacological treatment for major depressive disorder (MDD) in children and adolescent., Methods: We searched the published randomized controlled-trials to review fluoxetine efficacy and tolerability using the databases PubMed, EudraCT, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials for fluoxetine role in managing MDD in children and adolescents. A meta-analysis was conducted using the identified 7 clinical trials to assess efficacy using the outcomes: Children's Depression Rating Scale-Revised (CDRS-R), Clinical Global Impressions-Severity of Illness (CGI-S) and Clinical Global Impressions-Improvement (CGI-I) response rate. The risk of discontinuation due to adverse effects and common side effects were examined., Results: The mean difference in change from baseline for CDRS-R was -2.72 (95% confidence interval [CI], -3.96, -1.48) favoring fluoxetine treatment ( P < .001). Similarly, mean difference for CGI-S was -0.21 (95% CI, -0.36, -0.06). The risk ratio (RR) of discontinuing due to adverse events was 0.98 (95% CI, 0.54, 1.83), with RR for headache side effects 1.34 (95% CI, 1.03, 1.74) and rash 2.6 (95% CI, 1.32, 5.14)., Conclusion: Fluoxetine demonstrates significant improvements in symptom intensity control in young patients suffering from MDD and is considered well tolerated with similar rates of trials discontinuation; however, fluoxetine was associated with a higher risk of headache and rash side effects. These findings will guide psychiatrists and pharmacists in their clinical role for supporting the care of young mental health patients., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© Formulary Drug Reviews 2020.)