Neuroinflammation has been implicated in neurodegenerative diseases and acute brain injuries such as stroke. Monocyte chemotactic protein-1-induced protein-1 (Mcpip1) is a multifunction protein known to have pro-apoptotic or anti-apoptotic actions depending on the nature of experimental settings. However, its role in brain damage after asphyxia in the developing brain has not been studied. We, therefore, explored the role of Mcpip1 in brain injury after hypoxic-ischemia in neonatal mice. At postnatal day 7, Mcpip1-deficient and wild type mice underwent a carotid artery ligation and exposure to hypoxia (8% oxygen). After hypoxic-ischemic insult, we determined the time-course of apoptotic cell death and the expression levels of genes encoding proinflammatory factors. The impact of Mcpip1 on long-term brain damage was assessed 1 week post-hypoxic-ischemia by cresyl violet staining. We found caspase-3 activity was significantly increased in the ipsilateral brain tissues within 12-24 h after hypoxic-ischemia. There was a marked increase in the levels of mRNA transcripts encoding Mcpip1, TNFα, and CCL2 in the ipsilateral brain tissues 6-48 h after hypoxic-ischemia. We found hypoxic-ischemia-induced caspase-3 activity and the levels of the proinflammatory genes were attenuated in Mcpip1-knockout mice compared to wild type mice. Histological assessment revealed that hypoxic-ischemia-induced brain tissue loss was significantly attenuated in the hippocampus of Mcpip1-knockout mice than that of wild type mice (9.0 ± 5.6% vs. 33.9 ± 11.0%, P < 0.05). Our data suggest that Mcpip1 contributes to acute and delayed brain damage, in part, via regulation of neuroinflammation after hypoxic-ischemic insult in the developing mouse brain.