This study investigated the effects of the Sirtuin 1 (SIRT1) activator SRT2104 on hypoxia-induced white matter injury (WMI) in neonatal mice. A mouse model of neonatal WMI was established by exposing C57BL/6 mice to chronic hypoxia from postnatal Day 3 to Day 11. SRT2104 was administered intraperitoneally at doses of 2?mg/kg or 4?mg/kg from Day 11 for 5?days. Assessments included brain histology, myelination markers, oligodendrocyte differentiation, and behavioral tests. The results demonstrated SRT2104 at 4?mg/kg significantly reduced histological damage, promoted myelination by enhancing myelin basic protein and myelin-associated glycoprotein expression, and decreased oligodendrocyte apoptosis by reducing cleaved caspase-3 levels. Behavioral improvements were observed in locomotor activity, motor coordination, and cognitive function in treated mice. In summary, SRT2104 demonstrates protective effects against hypoxia-induced WMI by promoting oligodendrocyte survival and myelination, suggesting its potential as a therapeutic agent for WMI in neonatal hypoxia.