Objective To observe and evaluate the effect of esketamine use for cesarean section under general anesthesia on anesthesia and postpartum depression (PPD). Methods A total of 120 full-term primigravid women who underwent elective caesarean section under general anesthesia were selected. According to the random number table method, the women were divided into three groups (n=40): a continuous infusion of esketamine combined with propofol group (CEP group), a single intravenous bolus of esketamine combined with propofol continuous infusion group (BEP group), and a sevoflurane inhalation maintenance group (S group). After delivery of the fetus, the CEP group was continuously infused by pump with esketamine and propofol, the BEP group was subject to single intravenous bolus of esketamine and continuous infusion by pump of propofol, and the S group inhaled with sevoflurane for anesthesia maintenance. Their heart rate, systolic blood pressure and diastolic blood pressure at the time of admission to the operating room (T1), after anesthesia induction (T2), after delivery of the fetus (T3), at the end of the operation (T4), and at the time of recovery and leaving the operating room (T5); Visual Analogue Scale (VAS) scores during recovery after the operation (the resting state and active state), at postoperative 12 h, 24 h and 48 h; recovery time, postoperative nausea and vomiting, dizziness, and mental symptoms were recorded. The Edinburgh Postnatal Depression Scale (EPDS) scores and the incidence of PPD before surgery, at postoperative 3 days and 42 days were recorded. The total intraoperative dosages of esketamine in both the CEP and BEP groups were recorded. Results Compared with the S group, the CEP and BEP groups showed increases in heart rate, systolic blood pressure and diastolic blood pressure at T3, T4 and T5 (all P<0.05), decreases in VAS scores during recovery after the operation (the resting state and active state), at postoperative 12 h and 24 h (all P<0.05), and shortened recovery time (all P<0.05), and decreases in EPDS scores at postoperative 3 days and 42 days and the incidence of PPD (both P<0.05). No statistical difference was found in the heart rate, systolic and diastolic blood pressure at T1 and T2, VAS score at postoperative 48 h, preoperative EPDS score, PPD incidence, and the incidences of nausea and vomiting, dizziness, and mental symptoms (all P>0.05). Compared with the BEP group, the CEP group presented decreases in resting state VAS scores during recovery after surgery (P<0.05), and there was no statistical differences in heart rate, systolic blood pressure, diastolic blood pressure, recovery time, EPDS score, PPD incidence (all P>0.05). Conclusions Application of esketamine for cesarean section under general anesthesia can better maintain stable intraoperative vital signs, with fast recovery time and little pain at recovery. It can also effectively inhibit postpartum depression and reduce the incidence of PPD.