Objective To investigate the effect of low‑dose esketamine on postpartum depression (PPD) and postoperative analgesia in women undergoing cesarean section under general anesthesia. Methods A total of 141 women, aged 18‒40 years, body mass index 18‒35 kg/m2, American Society of Anesthesiologists grade Ⅱ, who underwent elective cesarean section under general anesthesia were enrolled. According to the random number table method, they were divided into two groups: an esketamine group (group S, n=71) and a control group (group C, n=70). Group S was given 0.25 mg/kg esketamine (diluted to 5 ml), 1 mg/kg propofol, and 4 μg/L remifentanil through target‑controlled infusion targeting effect‑site, as well as 0.6 mg/kg rocuronium through intravenous infusion. Group C was given 5 ml normal saline, 2 mg/kg propofol, and 4 μg/L remifentanil through target‑controlled infusion targeting effect‑site, as well as 0.6 mg/kg rocuronium through intravenous infusion. After delivery, both groups were kept under anesthesia with propofol and remifentanil. At the end of the operation, postoperative analgesia was achieved by bilateral transversus abdominis plane block under ultrasound guidance and postoperative intravenous controlled analgesia. The Edinburgh Postnatal Depression Scale (EPDS) scores 1 d before surgery, 7 d after surgery and 42 d after surgery, and the incidence of PPD of the two groups were recorded. The Visual Analogue Score (VAS) scores at postoperative 2, 12, 24, 48 h and the rate of rescue analgesia, postoperative adverse reactions and Apgar score 1 min and 5 min after birth of the two groups were recorded. Results Group S showed decreases in EPDS score 7 d after surgery and the incidence of PPD, compared with group C (all P<0.05). In group C, the EPDS scores 7 d after surgery and 42 d after surgery increased, compared with that 1 d before surgery (all P<0.05). In group S, the EPDS score 7 d after surgery decreased, compared with that 42 d after surgery (P<0.05). Compared with group C, group S presented decreases in VAS score at postoperative 2 h and the rate of rescue analgesia (all P<0.05). There was no statistical difference in Apgar score 1 min and 5 min and the incidence of adverse reactions between the two groups (all P>0.05). Conclusions Injection of esketamine at 0.25 mg/kg during the induction of general anesthesia can reduce the incidence of PPD 7 d after surgery, and provide good postoperative analgesia with a low incidence of adverse reactions. It can be safely used for cesarean section under general anesthesia, without significant effect on neonatal respiratory depression.