The Bcl‐2‐interacting death suppressor (Bis) protein is involved in antiapoptosis and antistress pathways. However, its roles after neonatal hypoxia–ischemia remain obscure. Therefore, we investigated the effects of Bis deletion on hippocampal cell death following neonatal hypoxia–ischemia. We transected the right common carotid artery of bis^+/+ and bis^−/− mice at postnatal Day 7 and subjected them to hypoxia for 35 min. Cresyl violet staining showed that hypoxia–ischemia induced progressive cell death in the hippocampi of bis^+/+ mice. Moreover, Bis was expressed in astrocytes, not microglia, in sham‐manipulated hippocampi of bis^+/+ mice, and was markedly enhanced after hypoxia–ischemia. Immunoblotting showed that Bis expression significantly increased 3 and 7 days following hypoxia–ischemia. Unexpectedly, 7 days after hypoxia–ischemia, the number of hippocampal NeuN‐positive cells was higher in the bis^−/− mice than in the bis^+/+ mice. We subsequently performed transcriptomic analysis and quantitative real time polymerase chain reaction to search for the underlying genes responsible for resistance to hypoxia–ischemia in the bis^−/− hippocampus. These studies showed that 6 h after hypoxia–ischemia, galectin 3 and filamin C levels increased to a lesser extent in the bis^−/− hippocampi compared with the bis^+/+ hippocampi. Finally, our in vitro hypoxia–ischemia model, using A172 glioma cells and primary astrocytes, showed that downregulation of Bis blocked the enhanced expression of galectin 3 after oxygen–glucose deprivation. This study demonstrated that Bis was upregulated in the astrocytes after hypoxia–ischemia. In addition, we showed that hippocampal neurons are less vulnerable to hypoxia–ischemia in mice lacking Bis, possibly because of the modulation of galectin 3 induction. © 2012 Wiley Periodicals, Inc.