Background: Vortioxetine had a positive effect on cognitive function and Health Related Quality of Life (HRQoL), while fluoxetine produced conflicting effects. The effects of study drugs on HRQoL and cognitive function in Metabolic Syndrome (MS) patients are uncertain. This study examines the effect of vortioxetine and fluoxetine in cognition and HRQoL with and without MS. Materials and Methods: Open-label, prospective, randomized controlled trial in the psychiatry department, patients were assigned either vortioxetine (group A) or fluoxetine (group B) and observed MS risk using International Diabetes Federation criteria, cognitive risk with the Saint Louis University Mental Status Examination score (SLUMS), and HRQoL using the RAND 36 questionnaire at baseline and at each visit (4,8,12,16,20 and 24 weeks). Results: We examined 122 MDD patients, sixty in Group A (26 had MS and 34 were non-MS) and sixty-two in group B (32 had MS and 30 were non-MS). Groups A and B were compared using an independent sample t-test. According to SLUMS score group B exhibited mild cognitive impairment in comparison to group A in both MS and non-MS patients. The RAND 36 questionnaire found better HRQoL in group A than group B for MS, including physical function, role physical, emotional well-being, energy/fatigue, emotion well-being, social function, and general health. In non-MS patients, group A had better physical function and role physical than group B. Conclusion: Vortioxetine shows greater potential as a therapeutic alternative for MDD patients with MS and cognitive function and improves HRQoL than fluoxetine.