Glucose hypometabolism in cortical structures after functional disconnection is frequently reported in patients with white matter diseases such as subcortical stroke. However, the molecular and cellular mechanisms have been poorly elucidated. Here we show, in an animal model of internal capsular infarct, that GABA-synthesizing reactive astrocytes in distant cortical areas cause glucose hypometabolism via tonic inhibition of neighboring neurons. We find that reversal of aberrant astrocytic GABA synthesis, by pharmacological inhibition and astrocyte-specific gene silencing of MAO-B, reverses the reduction in cortical glucose metabolism. Moreover, induction of aberrant astrocytic GABA synthesis by cortical injection of putrescine or adenovirus recapitulates cortical hypometabolism. Furthermore, MAO-B inhibition causes a remarkable recovery from post-stroke motor deficits when combined with a rehabilitation regimen. Collectively, our data indicate that cortical glucose hypometabolism in subcortical stroke is caused by aberrant astrocytic GABA and MAO-B inhibition and that attenuating cortical hypometabolism can be a therapeutic approach in subcortical stroke. Display omitted •Capsular infarct induces neuronal atrophy and reactive astrogliosis in motor cortex•Tonic GABA from reactive astrocytes suppresses neuronal glucose metabolism•Inhibition of MAO-B, the GABA-synthesizing enzyme, restores glucose metabolism•Combined therapy of MAO-B inhibitor and rehabilitation causes functional recovery Nam et al. demonstrate that excessive GABA from reactive astrocytes accounts for cortical glucose hypometabolism followed by subcortical stroke and impedes rehabilitation-aided motor functional recovery by aberrantly suppressing motor cortical neuronal activity. Thus, MAO-B, the astrocytic GABA-synthesizing enzyme, can be a therapeutic target for functional recovery after subcortical stroke.