Background: Treatment-resistant depression (TRD) is a major challenge in clinical psychiatry. Ketamine, an NMDA receptor antagonist, has emerged as a novel therapeutic option due to its rapid antidepressant effects. This study aimed to evaluate the efficacy and safety of ketamine in patients with TRD. Methods: This was a prospective, open-label clinical study conducted on patients diagnosed with major depressive disorder not responding to at least two adequate antidepressant trials. Intravenous ketamine (0.5 mg/kg) was administered over 40 minutes twice weekly for two weeks. Patients were assessed using the Hamilton Depression Rating Scale (HDRS) and Montgomery-Asberg Depression Rating Scale (MADRS) at baseline, Day 3, Day 7, and Day 14. Adverse effects were monitored using a standardized checklist. Results: A total of 40 patients with TRD were enrolled. Mean HDRS scores reduced significantly from 25.3±3.2 at baseline to 12.4±2.8 at Day 14 (p<0.001). MADRS scores showed a similar decline from 32.1±4.5 to 14.8±3.7 (p<0.001). Response rate (≥50% reduction in HDRS) was observed in 67.5% of patients, and remission (HDRS ≤7) in 22.5%. Adverse effects were mild and transient, with dissociation (20%), dizziness (12.5%), and nausea (10%) being most common. Conclusion: Intravenous ketamine demonstrates rapid and significant antidepressant effects in patients with treatment-resistant depression and is generally well-tolerated. Further controlled studies with larger sample sizes and long-term follow-up are warranted to establish its sustained efficacy and safety.