Objective To investigate the effect of combined use of esketamine (ESK) in epidural analgesia pump on labor analgesia and postpartum depression (PPD). Methods A total of 81 puerpera who underwent labor analgesia in the General Hospital of Southern Theatre Command, PLA from January 2020 to Jun 2022 were selected. According to the random number table method, they were divided into two groups: a control group (n=40) and an esketamine group (ESK group, n=41). The total volume of the analgesia pump was 140 ml. For the control group, the analgesia pump contained 0.75 g/L bupivacaine and 0.5 mg/L sufentanil. In addition to bupivacaine and sufentanil at the indicated concentrations, 50 mg ESK was added into the analgesia pump of the esketamine group. Then epidural anesthesia was performed, where the pumping speed was 5 ml/h, and the dosage of single pressing was 5 ml. The pumping interval was at least 15 min, with the maximum pumping speed of 15 ml/h. Primary outcomes included Visual Analogue Scale (VAS) scores and anxiety scores before analgesia, 30 min after analgesia and after delivery, Edinburgh Postnatal Depression Scale (EPDS) scores on day 42 after delivery and the incidence of PPD. Secondary outcomes included heart rate, mean artery pressure (MAP), systolic blood pressure (SBP) and diastolic blood pressure (DBP) before analgesia, 30 min after analgesia and after delivery. Results Compared with the control group, the ESK group showed decreases in heart rate, MAP, SBP and DBP (all P<0.05) and VAS scores and anxiety scores 30 min after analgesia and after delivery (all P<0.05). Furthermore, on day 42 after delivery, compared with the control group, the EPDS scores and the incidence of PPD were reduced in the ESK group (all P<0.05). There were no statistical differences in each indicator before analgesia between the two groups (all P<0.05). Conclusions The combined use of esketamine in labor analgesia can remarkably alleviate the pain in delivery and reduce the incidence and severity of PPD.