Postpartum depression (PPD) is the most common type of puerperal mental syndrome and affects maternal physical and mental health and even the growth and development of infants. Paeoniflorin exerts a potential antidepressive effect; however, the functional roles and potential mechanisms of paeoniflorin in PPD are still largely unknown. PPD rat models were prepared by withdrawing hormone‑simulated pregnancy (HSP), and subjects were treated with paeoniflorin and fluoxetine or plasmids. The sucrose preference test (SPT), forced swimming test (FST) and tail suspension test (TST) were used to monitor depression‑like behavior in rats. A radioimmunoassay was utilized for estradiol (E2) and progesterone (P) measurements. ELISA was performed to detect serum corticosterone (Cor), hippocampal allopregnanolone (Allo), IL‑1β and TNF‑α levels. Expression of the E2 receptors ERα and ERβ was detected by qPCR. Western blotting was used to detect TSPO, BDNF and mTOR phosphorylation. Paeoniflorin drastically increased the sucrose preference of rats while decreasing the immobility time in the FST and TST in PPD models. Moreover, paeoniflorin intervention upregulated serum E2, hippocampal Allo, ERα, and ERβ levels but degraded P, serum Cor, IL‑1β, TNF‑α and ERα/ERβ levels. Mechanistically, paeoniflorin promoted TSPO and BDNF‑mTOR pathway activation in PPD rats. Furthermore, suppression of TSPO or the BDNF‑mTOR pathway partially reversed the effects of paeoniflorin on depression‑like behaviors, hormone levels, and inflammatory cytokine release. Paeoniflorin may improve symptoms of PPD by regulating the TSPO and BDNF‑mTOR pathways, indicating that paeoniflorin may be an effective anti‑PPD and antidepressant drug, providing evidence for the future treatment of PPD.