This study investigates the role of astrocytic ALKBH5 in stress response and its impact on depressive-like behaviors in mice. ALKBH5, an RNA demethylase of N6-methyladenosine (m6A), is upregulated in the blood and prefrontal cortex (PFC) of major depressive disorder (MDD) patients and mouse models of depression. Astrocytic ALKBH5 is more sensitive to stress than neuronal or endothelial cell ALKBH5. Selective deletion of ALKBH5 in astrocytes, but not in neurons or endothelial cells, produces antidepressant-like behaviors. Astrocytic ALKBH5 in the PFC regulates depression-related behaviors bidirectionally, maintaining neuronal morphology, calcium activity, and glutamatergic transmission through m6A modifications of glutamate transporter-1 (GLT-1). Additionally, S-adenosylmethionine (SAMe), which sustains m6A modification, produces antidepressant-like effects. These findings suggest that astrocytic epigenetic changes, particularly m6A modifications, contribute to depressive-like behaviors and that targeting astrocytic ALKBH5 may be a therapeutic approach for depression.This study investigates the role of astrocytic ALKBH5 in stress response and its impact on depressive-like behaviors in mice. ALKBH5, an RNA demethylase of N6-methyladenosine (m6A), is upregulated in the blood and prefrontal cortex (PFC) of major depressive disorder (MDD) patients and mouse models of depression. Astrocytic ALKBH5 is more sensitive to stress than neuronal or endothelial cell ALKBH5. Selective deletion of ALKBH5 in astrocytes, but not in neurons or endothelial cells, produces antidepressant-like behaviors. Astrocytic ALKBH5 in the PFC regulates depression-related behaviors bidirectionally, maintaining neuronal morphology, calcium activity, and glutamatergic transmission through m6A modifications of glutamate transporter-1 (GLT-1). Additionally, S-adenosylmethionine (SAMe), which sustains m6A modification, produces antidepressant-like effects. These findings suggest that astrocytic epigenetic changes, particularly m6A modifications, contribute to depressive-like behaviors and that targeting astrocytic ALKBH5 may be a therapeutic approach for depression.