Postpartum depression is a common disabling psychosocial disorder that could have adverse effects on the life of the mother, infant, and family. The present study was conducted to evaluate the effect of ketamine on preventing postpartum depression in women undergoing caesarian sections considering the relatively known positive effect of ketamine on major depression. The present double-blind, randomized clinical trial was conducted on 134 women undergoing scheduled caesarian sections. Participants were randomly allocated into two groups of control and intervention. To induce anesthesia, 1–2 mg/kg of body weight of Nesdonal and 0.5 mg/kg of body weight of ketamine were used in the intervention group, while only 3–5 mg/kg of body weight Nesdonal was administered in the control group. Data were gathered using the Edinburgh Postnatal Depression Scale (EPDS) in three stages: before the caesarian section and two and four weeks after the caesarian section. Data were analyzed using variance analysis with repeated measures and the Chi-square test. Results of the present study showed that the mean (± standard deviation) of the depression score in the intervention and control groups were 13.78±3.87 and 13.79±4.78(p = 0.98) before the caesarian section, 11.82±3.41 and 14.34±4.29 (p < 0.001) two weeks after and 10.84±3.48 and 13.09±3.79 (p = 0.001) four weeks after the caesarian section, respectively. Using ketamine in the induction of general anesthesia could be effective in preventing postpartum depression. However, further studies are required to strengthen these findings.