Neonatal maternal deprivation (MD) leads to depressive-like behaviors by promoting hippocampal neuronal apoptosis, but whether and how ERK1/2 signaling participates in MD-induced hippocampal neuronal apoptosis remains unclear. We therefore explored the role of ERK1/2 signaling pathway in neonatal MD-induced depression. Neonatal rats were divided into control group, PD group given intraperitoneal injections of MAPKK inhibitor (PD98059), MD group, and MD+PD group. The neonatal MD model was confirmed by behavioral tests. Compared with controls, MD group showed increased hippocampal neuronal apoptosis, higher mRNA expressions of Bax, caspase-3 and caspase-9mRNAs, and lower expression of Bcl-2 and BDNF. Similarly, compared with controls, MD group showed higher protein expression and wider distribution of Bax, caspase-3, caspase-9 and Cytochrome C but lower protein expression of Bcl-2, p-CREB, BDNF and p-ERK1/2. The changes in the MD group were reversed in the MD+PD group, except that p-ERK1/2 expression was decreased. In conclusion, MD-induced depression is associated with hippocampal neuronal apoptosis, which may be mediated by the ERK1/2 signaling pathway. These findings may provide novel avenues for depression therapy.