The establishment of a chronic inflammatory state in the adipose tissue contributes to obesity-associated insulin resistance. Hence, disrupting the inflammatory response elicited by obesity remains a relevant target to tackle the modern-world pandemic. We evaluated the anti-inflammatory and insulin-sensitizing effect of Calafate (Berberis microphylla) by producing and characterizing a polyphenol-pure Calafate extract (PPCE). C57BL/6 mice fed with cafeteria diet for 14 weeks were administered PPCE (50 mg/Kg/day) for 4 weeks. PPCE administration rescued glucose tolerance and insulin-elicited AKT phosphorylation in white adipose tissue of diet-induced insulin-resistant mice. Furthermore, the cafeteria diet-induced expression of TNF-alpha and F4/80 was attenuated by PPCE administration, suggesting that PPCE rescues insulin sensibility by ameliorating the obesity-associated inflammatory state. Altogether, our data shows that Calafate represents a natural source of polyphenols with glucose tolerance-improving properties in vivo, suggesting a potential use of PPCE as a complementary tool against insulin resistance.