The Mela Rosa dei Monti Sibillini is an ancient apple variety cultivated by Romans in the foothills of the Sibillini Mountains, central Italy, showing potential as a source of nutraceuticals. The purpose of this study was to evaluate the protective effects of the hydroalcoholic extracts from the peel (APE) and pulp (APP) of this fruit in an animal model of transient global ischemia. Chemical constituents were analyzed by liquid chromatography–mass spectrometry (LC-DAD-MSn) indicating several polyphenols such as B-type procyanidins, quercetin derivatives and hydroxycinnamic acids as the main bioactive components. Acute pre-treatment of extracts (30 mg/kg, i.p.) significantly decreased the brain levels of the pro-inflammatory cytokines IL-1β (p < 0.01) and TNF-α (p < 0.001 and p < 0.01 for APE and APP, respectively), the expression of caspase-3 (p < 0.01, For APE) and MDA (p < 0.05), a lipid peroxidation biomarker in rats. Both extracts restricted the pathological changes of the brain induced by ischemic stroke in hematoxylin and eosin assay. Moreover, they improved the scores of behavioral tests in grid-walking and modified neurological severity scores (mNSS) tests. In conclusion, these results proved this ancient Italian apple is a source of nutraceuticals able to protect/prevent damage from brain ischemia.