Background: There is a paucity of studies exploring the role of ketamine as augmenting agent to conventional antidepressants. Materials and methods: Sixty patients with major depressive disorder (MDD) were randomized to 4 weeks’ double-blind treatment with escitalopram 10 mg/day + single-dose intravenous (IV) ketamine (0.5 mg/kg over 40 minutes) or escitalopram 10 mg/day + placebo (0.9% IV saline). Depressive symptoms were measured using the Montgomery–Asberg depression rating scale (MADRS), adverse effects were measured with the brief psychiatric rating scale (BPRS), young mania rating scale (YMRS), and clinician administered dissociative states scale (CADSS). Patients were assessed at baseline, 4, 24, and 48 hours and 7 days and 28 days. Response (50% MADRS score reduction) was the primary outcome. Results: The MADRS scores showed significant reduction in the group receiving ketamine as compared to group receiving placebo at 4, 24, and 48 hours, 1 week, and 28 days (p < 0.001). By 4 weeks, compared to escitalopram + placebo-treated patients, more of escitalopram + ketamine-treated patients responded (80% vs 20%) and remitted (21.67% vs 0%). Rapid response was evident at 4 hours in ketamine group as compared to placebo (36.67% vs 0%). Both CADSS and YMRS scores were significantly higher (p < 0.001) in the ketamine group as compared to the placebo group at 4 hours but not at 24 and 48 hours and 7 and 28 days. Conclusion: Single-dose IV ketamine as an add-on to 10 mg/day escitalopram is efficacious, resulting in more rapid and robust response over 4 weeks. Dissociative and mania-like symptoms emerging post-infusion are mild and transient, not warranting treatment discontinuation. Further research into the role of ketamine augmentation in MDD is required for its clinical applicability.