A strong body of research has defined the role of excitotoxic glutamate in animal models of brain ischemia and stroke; however, clinical trials of glutamate receptor antagonists have demonstrated their limited capacity to prevent brain damage following ischemia. We propose that astrocyte-neuron signaling represents an important modulatory target that may be useful in mediating damage following stroke. To assess the impact of astrocyte signaling on damage following stroke, we have used the astrocyte-specific dominant-negative SNARE mouse model (dnSNARE). Recent findings have shown that the astrocytic SNARE signaling pathway can affect neuronal excitability by regulating the surface expression of NMDA receptors. Using focal photothrombosis via the Rose Bengal method, as well as excitotoxic NMDA lesions, we show that dnSNARE animals exhibited a sparing of damaged tissue quantified using Nissl and NeuN staining. At the same time point, animals were also tested in behavioral tasks that probe the functional integrity of stroke- or lesion-damaged motor and somatosensory areas. We found that dnSNARE mice performed significantly better than littermate controls on rung walk and adhesive dot removal tasks following lesion. Together, our results demonstrate the important role of astrocytic signaling under ischemic conditions. Drugs targeting astrocyte signaling have a potential benefit for the outcome of stroke in human patients by limiting the spread of damage.