Metabolic disorders related to obesity and type 2 diabetes are associated with aggravated cerebrovascular damages during stroke. In particular, hyperglycemia alters redox and inflammatory status, leading to cerebral endothelial cell dysfunction, blood-brain barrier (BBB) disruption and brain homeostasis loss. Polyphenols constitute the most abundant dietary antioxidants and exert antiinflammatory effects that may improve cerebrovascular complications in stroke. This study evaluated the effects of the characterized polyphenol-rich extract of Antirhea borbonica medicinal plant and its major constituent caffeic acid on a high-fat diet (HFD)-induced obesity mouse model during ischemic stroke, and murine bEnd3 cerebral endothelial cells in high glucose condition. In vivo, polyphenols administered by oral gavage for 12 weeks attenuated insulin resistance, hyperglycemia, hyperinsulinemia and dyslipidemia caused by HFD-induced obesity. Polyphenols limited brain infarct, hemorrhagic transformation and BBB disruption aggravated by obesity during stroke. Polyphenols exhibited anti-inflammatory and antioxidant properties by reducing IL-1β, IL-6, MCP-1, TNF-α and Nrf2 overproduction as well as total SOD activity elevation at the cerebral or peripheral levels in obese mice. In vitro, polyphenols decreased MMP-2 activity that correlated with MCP-1 secretion and ROS intracellular levels in hyperglycemic condition. Protective effects of polyphenols were linked to their bioavailability with evidence for circulating metabolites including caffeic acid, quercetin and hippuric acid. Altogether, these findings show that antioxidant polyphenols reduced cerebrovascular, inflammatory and metabolic disorders aggravated by obesity in a mouse model of stroke. It will be relevant to assess polyphenol-based strategies to improve the clinical consequences of stroke in the context of obesity and diabetes.