Background:The study aimed to compare the efficacy and safety of agomelatine and escitalopram in patients with Major Depressive Disorder (MDD) over 12 weeks. The primary objective was to evaluate changes in depressive symptoms using the Hamilton Depression Rating Scale (HAM-D), while secondary outcomes included improvements in the Montgomery-Asberg Depression Rating Scale (MADRS) and Clinical Global Impression-Severity (CGI-S) scores. Additionally, the study assessed adverse events and discontinuation rates to compare the tolerability of both medications.Materials and Methods: This randomized, double-blind, parallel-group clinical trial enrolled 100 patients diagnosed with MDD based on DSM-5 criteria. Patients were randomly assigned to either the agomelatine group (25–50 mg/day) or the escitalopram group (10–20 mg/day) for 12 weeks. Treatment efficacy was assessed using HAM-D, MADRS, and CGI-S scores at baseline, Week 2, Week 4, Week 8, and Week 12. Safety was evaluated based on reported adverse events and laboratory assessments. Data were analyzed using SPSS, with statistical significance set at p< 0.05.Results: Both groups showed significant reductions in HAM-D and MADRS scores over the study period, with no statistically significant differences between them (p> 0.05). The mean HAM-D score at Week 12 was 7.8 ± 2.9 in the agomelatine group and 9.3 ± 3.1 in the escitalopram group (p = 0.18), indicating comparable efficacy. Similarly, MADRS scores improved to 10.5 ± 3.6 and 12.2 ± 3.8 in the agomelatine and escitalopram groups, respectively (p = 0.21). Adverse events were reported in both groups, with headache, nausea, and dizziness being the most common. Agomelatine had a slightly higher incidence of elevated liver enzymes (8% vs. 4%, p = 0.34), while escitalopram was associated with a higher incidence of sexual dysfunction. Treatment discontinuation rates were similar between the two groups.Conclusion: Agomelatine and escitalopram demonstrated similar efficacy in reducing depressive symptoms over 12 weeks. Agomelatine offered advantages in sleep regulation and lower sexual side effects but required liver function monitoring. Escitalopram remained a well-tolerated and effective SSRI, though it had a higher incidence of withdrawal symptoms and sexual dysfunction. The choice between these medications should be based on individual patient needs, comorbid conditions, and tolerability profiles.