Vilazodone is a new molecule approved for major depressive disorder (MDD). This report focuses on the efficacy and tolerability of vilazodone for MDD. MEDLINE, EMBASE, and Cochrane Library were searched. A total of 1,930 patients from four trials were included. A significant improvement in the Montgomery–Asberg Depression Rating Scale (MADRS) total score was seen as early as week 2 ( P<0.01) in vilazodone-treated patients. The results showed a higher rate of MADRS response with vilazodone compared with placebo ( P<0.001). There were also greater improvements in the Hamilton Rating Scale for Anxiety as well as the Clinical Global Impressions (severity of illness and improvement of illness) scores from baseline in vilazodone-treated patients compared to placebo patients ( P<0.001). Discontinuation rates due to adverse events were higher with vilazodone than placebo ( P=0.0002). The most common adverse events of vilazodone were vomiting, nausea, diarrhea, insomnia, somnolence, dizziness, and dry mouth ( P<0.05). Treatment-related effects on sexual function were mild compared to placebo in men ( P=0.03). In conclusion, 40 mg/day of vilazodone had a rapid onset of response and showed good improvement in anxiety symptoms as well as good tolerability during short-term treatment (8–10 weeks) for MDD. Further studies should focus on the efficacy and tolerability of vilazodone over a longer duration and should utilize active comparators.