Abstract: Objective To investigate the role of phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) signaling pathway for umbilical cord-derived mesenchymal stem cells (UC-MSCs) treating in neonatal rats with hypoxia-ischemia brain damage (HIBD). Methods P10 SD rats were divided into sham group, MSCs group, inhibitor (LY 294002) group (LY group) and HIBD group randomly. To establish a neonatal rat model of HIBD, UC-MSCs labeled with Brd U were transplanted into the lateral ventricle of rats. At 24 and 48 h after transplantation, the number of apoptotic cells was detected by TUNEL, while the expression of caspase3 protein and phosphorylation of Akt (P-Akt) were quantified by Western blot. Results At 24 and 48 h after transplantation, both the apoptotic cells and caspase3 protein expression in MSCs group were less than those in LY group and HIBD group ( P＜0.05), while the expression of P-Akt was higher than those in LY group and HIBD group ( P＜0.05), and with the passage of time after transplantation, the expression of each index showed a downward trend. Conclusion The apoptotic cells of brain and the expression of caspase3 protein decrease, while the expression of P-Akt increase. PI3K/Akt signaling pathway may be an important mechanism for UC-MSCs transplantation in HIBD rats.