Background: Apigenin, as a flavonoid, can be protective against oxidative damage in hypoxic events due to its antioxidant properties. Here, we have investigated the neuroprotective effects of apigenin in an ex vivo model of ischemic damage, using cerebellar slices from postnatal day (P)8–12 reporter mice to identify oligodendrocytes (SOX10-EGFP) and astrocytes (GFAP-EGFP). Methods: Apigenin (10 and 20 μM) was administered preventively at 60 min prior to and during inducing ischemic damage by oxygen and glucose deprivation (OGD); controls were maintained with glucose and normoxia (OGN). Results: OGD induced a marked retraction of oligodendroglial processes without reducing the oligodendrocyte number. This structural disruption was prevented by apigenin; notably, 10 μM apigenin blocked process retraction, whereas 20 μM did not, indicating a dose-dependent effect on the oligodendroglial morphology. Consistent with this, MBP and NF70 immunofluorescence analyses of axonal myelination demonstrated that OGD caused a significant loss of myelin sheaths, and this was prevented by pre-treatment with apigenin. In addition, apigenin prevented astrocyte reactivity induced by OGD, as assessed by increased GFAP-EGFP expression and decreased expression of glutamine synthetase. Moreover, immunofluorescence for calbindin indicated that apigenin protected Purkinje neurons from ischemic damage. Conclusions: These results demonstrate that apigenin is neuroprotective in ischemia and this is associated with modulation of astrocyte reactivity and maintenance of oligodendrocyte and myelin integrity.