Neonatal brain injury, especially severe injury induced by hypoxia-ischemia (HI), causes mortality and long-term neurological impairments. Our previous study demonstrated activation of CD11b + myeloid cells, including residential microglial cells (MGs) and infiltrating monocyte-derived macrophages (MDMs) in a murine model of hypoxicischemic brain damage (HIBD), with unknown functions. Here, we study the differences in the phagocytic function of MGs and MDMs to clarify their potential roles after HIBD. HI was induced in 9-10-day postnatal mice. On days 1 and 3 after injury, pathological and neurobehavioral tests were performed to categorize the brain damage as mild or severe. Flow cytometry was applied to quantify the dynamic change in the numbers of MGs and MDMs according to the relative expression level of CD45 in CD11b + cells. CX 3 CR 1 GFP CCR 2 RFP double-transformed mice were used to identify MGs and MDMs in the brain parenchyma after HIBD. Lysosome-associated membrane protein 1 (LAMP1), toll-like receptor 2 (TLR2), CD36, and transforming growth factor (TGF-β) expression levels were measured to assess the underlying function of phagocytes and neuroprotective factors in these cells. The FITC-dextran 40 phagocytosis assay was applied to examine the change in phagocytic function under oxygen-glucose deprivation (OGD) in vitro. We found that neonatal HI induced a different degree of brain damage: mild or severe injury. Compared with mildly injured animals, mice with severe injury had lower weight, worse neurobehavioral scores, and abnormal brain morphology. In a severely injured brain, CD11b + cells remarkably increased, including an increase in the MDM population and a decrease in the MG population. Furthermore, MDM infiltration into the brain parenchyma was evident in CX 3 CR 1 GFP CCR 2 RFP double-transformed mice. Mild and severe brain