Spreading depolarizations (SDs) have been linked to infarct volume expansion following ischemic stroke. Therapeutic hypothermia provides a neuroprotective effect after ischemic stroke. This study aimed to evaluate the effect of hypothermia on the propagation of SDs and infarct volume in an ischemic swine model. Through left orbital exenteration, middle cerebral arteries were surgically occluded (MCAo) in 16 swine. Extensive craniotomy and durotomy were performed. Six hypothermic and five normothermic animals were included in the analysis. An intracranial temperature probe was placed right frontal subdural. One hour after ischemic onset, mild hypothermia was induced and eighteen hours of electrocorticographic (ECoG) and intrinsic optical signal (IOS) recordings were acquired. Postmortem, 4 mm-thick slices were stained with 2,3,5-triphenyltetrazolium chloride to estimate the infarct volume. Compared to normothermia (36.4 ± 0.4°C), hypothermia (32.3 ± 0.2°C) significantly reduced the frequency and expansion of SDs (ECoG: 3.5 ± 2.1, 73.2 ± 5.2% vs. 1.0 ± 0.7, 41.9 ± 21.8%; IOS 3.9 ± 0.4, 87.6 ± 12.0% vs. 1.4 ± 0.7, 67.7 ± 8.3%, respectively). Further, infarct volume among hypothermic animals (23.2 ± 1.8% vs. 32.4 ± 2.5%) was significantly reduced. Therapeutic hypothermia reduces infarct volume and the frequency and expansion of SDs following cerebral ischemia.