Ketamine, a commonly used general anesthetic, can produce rapid and sustained antidepressant effect. However, the efficacy and safety of the perioperative application of ketamine on postoperative depression remains uncertain. We performed a meta-analysis to determine the effect of perioperative intravenous administration of ketamine on postoperative depression. Randomized controlled trials comparing ketamine with placebo in patients were included. Primary outcome was postoperative depression scores. Secondary outcomes included postoperative visual analog scale (VAS) scores for pain and adverse effects associated with ketamine. Fifteen studies with 1697 patients receiving ketamine and 1462 controls were enrolled. Compared with the controls, the ketamine group showed a reduction in postoperative depression scores, by a standardized mean difference (SMD) of −0.97, 95% confidence interval [CI, −1.27, −0.66], P < 0.001, I² = 72% on postoperative day (POD) 1; SMD−0.65, 95% CI [−1.12, −0.17], P < 0.001, I² = 94% on POD 3; SMD−0.30, 95% CI [−0.45, −0.14], P < 0.001, I² = 0% on POD 7; and SMD−0.25, 95% CI [−0.38, −0.11], P < 0.001, I² = 59% over the long term. Ketamine reduced VAS pain scores on POD 1 (SMD−0.93, 95% CI [−1.58, −0.29], P = 0.005, I² = 97%), but no significant difference was found between the two groups on PODs 3 and 7 or over the long term. However, ketamine administration distinctly increased the risk of adverse effects, including nausea and vomiting (risk ratio [RR] 1.40, 95% CI [1.12, 1.75], P = 0.003, I² = 30%), headache (RR 2.47, 95% CI [1.41, 4.32], P = 0.002, I² = 19%), hallucination (RR 15.35, 95% CI [6.²4, 37.34], P < 0.001, I² = 89%), and dizziness (RR 3.48, 95% CI [2.68, 4.50], P < 0.001, I² = 89%) compared with the controls. In conclusion, perioperative application of ketamine reduces postoperative depression and pain scores with increased risk of adverse effects.