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Background Hypoxia-ischemia is an important cause of brain injury and neurological morbidity in the newborn infants. The activity of glycogen synthase kinase-3β (GSK-3β) is up-regulated following neonatal stroke. Tideglusib is a GSK-3β inhibitor which has neuroprotective effects against neurodegenerative diseases in clinical trials. However, the effect of tideglusib on hypoxic-ischemic (HI) brain injury in neonates is still unknown. Methods Postnatal day 7 (P7) mouse pups subjected to unilateral common carotid artery ligation followed by 1 h of hypoxia or sham surgery was performed. HI animals were administered tideglusib (5 mg/kg) or vehicle intraperitoneally 20 min prior to the onset of ischemia. The brain infarct volume and whole brain images, were used in conjunction with Nissl staining to evaluate the protective effects of tideglusib. Protein levels of glial fibrillary acidic protein (GFAP), Notch1, cleaved caspase-3/9, phosphorylated signal transducer and activator of transcription 3 (STAT3), GSK-3β and protein kinase B (Akt) were detected to identify potentially involved molecules. Results Tideglusib significantly reduced cerebral infarct volume at both 24 h and 7 days after HI injury. Tideglusib also increased phosphorylated GSK-3β(Ser9) and Akt(Ser473), and reduced the expression of GFAP and p-STAT3(Tyr705). In addition, pretreatment with tideglusib also enhanced the protein level of Notch1. Moreover, tideglusib reduced the cleavage of pro-apoptotic signal caspase proteins, including caspase 3 and caspase 9 following HI. Conclusion These results indicate that tideglusib shows neuroprotection against hypoxic-ischemic brain injury in neonatal mice. General significance Tideglusib is a potential compound for the prevention or treatment of hypoxic-ischemic brain injury in neonates. [ABSTRACT FROM AUTHOR]