Polyphenols are natural compounds with promising prophylactic and therapeutic applications. However, their methods of extraction, using organic solvents, may prove to be unsuitable for daily consumption or for certain medical indications. Here, we describe the neuroprotective effects of grape polyphenols extracted in an eco-sustainable manner in a rat model of neonatal hypoxia-ischemia (NHI). Polyphenols (resveratrol, pterostilben and viniferin) were obtained using a subcritical water extraction technology to avoid organic solvents and heavy metals associated with chemical synthesis processes. A resveratrol or a polyphenol cocktail were administered to pregnant females at a nutritional dose and different time windows, prior to induction of NHI in pups. Reduced brain edema and lesion volumes were observed in rat pups whose mothers were supplemented with polyphenols. Moreover, the preservation of motor and cognitive functions (including learning and memory) was evidenced in the same animals. Our results pave the way to the use of polyphenols to prevent brain lesions and their associated deficits that follow NHI, which is a major cause of neonatal death and disabilities.