Objective To evaluate the effect of epidural labor analgesia combined with esketamine on analgesic effect and postpartum depression (PPD) in primiparous women who delivered vaginally. Methods A total of 300 primiparous women who delivered vaginally in Changsha Maternal and Child Health Hospital Affiliated to Hunan Normal University from January to June 2022 were selected. According to whether they received labor analgesia, they were divided into two groups: a natural delivery group (group Z, n=58) and a labor analgesia group (n=242). According to the random number table method, the labor analgesia group was sub‑divided into two groups: a routine group (group C, n=119) and an esketamine group (group K, n=123). Their Visual Analogue Scale (VAS) scores were recorded before labor analgesia, during labor, and at postoperative 2 h, 24 h, and 48 h. The Edinburgh Postnatal Depression Scale (EPDS) scores and the incidence of PPD were also recorded when the primiparous women entered the delivery room, at postoperative 2 h, and on postoperative 1, 7, and 42 days. The levels of oestrogen, progesterone, 5‑hydroxytryptamine (5‑HT), and cortisol were detected when the primiparous women entered the delivery room, and at postoperative 1 day. Results Compared with group Z, group C and group K showed decreases in VAS score during labor, and decreases in EPDS scores on postoperative 1, 7, and 42 days, with a reduced PPD incidence at postoperative 2 h, 1 day and 7 days (all P<0.05). Group C and group K also presented increases in the levels of estrogen, progesterone, 5‑HT and cortisol on postoperative 1 day, compared with group Z (all P<0.05). The EPDS scores on postoperative 1 day and 42 days and the PPD incidence on postoperative 1 day in group K were lower than those in group C (all P<0.05). The levels of progesterone and cortisol on postoperative 1 day in group K were higher than those in group C (all P<0.05). There was no statistical difference in other indicators (all P>0.05). Conclusions Epidural labor analgesia combined with ketamine does not improve analgesic effect, but can further reduce the risk of postpartum depression.