Ischemic stroke (IS) remains one of the leading causes of death and disability worldwide. The pathogenic mechanisms underlying the development of this condition are multiple and complex, which is the primary reason why an effective therapy is still lacking.

The beneficial effects of natural compounds against cardiovascular diseases and ischemic stroke have been extensively studied. In this article, we examined the association between the most studied polyphenols and stroke protection in terms of prevention, acute phase impact, and rehabilitation. We described experimental and epidemiological studies reporting the role of flavonols, phenolic acid, and stilbenes on ischemic mechanisms leading to stroke.

We analyzed the main animal models used to evaluate the impact of these micronutrients on cerebral blood flow and the molecular pathways involved in oxidative stress and inflammation modulation, such as sirtuins. We highlighted significant clinical studies showing how the persistent use of polyphenols is clinically relevant in reducing vascular risk factors for ischemic stroke, such as atrial fibrillation.

Interestingly, different types of polyphenols provide varying protections to the brain by activating different pathways and mechanisms, such as the antithrombotic effect of onochiol. For this reason, we discussed their appropriate integrative use as a possible therapeutic alternative against stroke.