The therapeutic hypothermia for acute stroke might play an important role in neuroprotection. However, the mechanisms are complex and not yet fully understood. Here we investigated the role of adenosine A1 receptors in mild hypothermia-mediated neuroprotection during the acute phase of ischemia. Severe ischemia-induced neurosynaptic impairment was mimicked by oxygen-glucose deprivation at normothermia (36°C) with extracellular recordings or whole-cell patch clamp recordings in acute hippocampal slices in mice. Mild hypothermia (32°C) induced the protection of synaptic transmission by activating adenosine A1 receptors. Moderate hypothermia (28°C) caused additional neuroprotective effects by extending the onset time to the anoxic event; however, this effect was not associated with adenosine A1 receptor. The response of adenosine-induced inhibition of hippocampal synaptic transmission was increased by lowering temperature to 32°C or 28°C. This study might reveal the involvement of adenosine in the therapeutic hypothermia (usually done at 32-33 °C) for acute stroke.