Aim: The aim of this study was to compare the efficacy and safety of Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) in treating patients diagnosed with Major Depressive Disorder (MDD), focusing on the response rates, side effects, and overall improvement in mood and quality of life. Materials and Methods: This prospective, randomized, open-label, parallel-group study included 120 patients with MDD. Participants were randomly assigned to receive either SSRIs (fluoxetine, sertraline, or escitalopram) or SNRIs (venlafaxine or duloxetine) over 8 weeks. The primary outcome was the change in Hamilton Depression Rating Scale (HAM-D) score from baseline to 8 weeks. Secondary outcomes included response rate (≥50% reduction in HAM-D), remission rate (HAM-D ≤7), side effects (measured using the FIBSER scale), and quality of life (assessed with the WHOQOL-BREF scale). Results: Both treatment groups demonstrated significant reductions in HAM-D scores, with no significant difference in scores between SSRIs (5.8 ± 2.0) and SNRIs (5.7 ± 2.1) at Week 8 (p=0.89). The response rates were 70% for the SSRI group and 75% for the SNRI group (p=0.45). The remission rates were 50% for the SSRI group and 53.3% for the SNRI group (p=0.70). Common side effects included nausea, insomnia, and dizziness, with no significant differences between groups. Both groups showed significant improvements in all domains of the WHOQOL-BREF scale (p<0.001). Conclusion: SSRIs and SNRIs were found to be equally effective in reducing depressive symptoms and improving quality of life in patients with MDD. Both treatments had similar efficacy and safety profiles, making them both viable options for treating MDD, with patient preferences and tolerability potentially guiding treatment decisions.