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[Display omitted] • Pistacia vera L. shell extract was optimized by a response surface methodology approach. • The HPLC/ESI-MS/MS allowed to identify the main constituents of the optimized extract. • The optimized extract exhibited a significant antioxidant/antiradical activity. • The optimized extract exhibited a notable α-amylase and α-glucosidase inhibitory activity. • Intestinal cell viability (Caco-2, HT29-MTX) was not affected by the optimized extract. Pistacia vera shells, an abundant agricultural by-product, are a rich source of undiscovered bioactive compounds. This study employed a response surface methodology (RSM) approach to optimize the microwave-assisted extraction of antioxidants. The highest total phenolic content, and antioxidant activity were achieved under the optimized extraction conditions (20 % ethanol, 1000 W, 135 s, and solvent-to-solid ratio of 27 mL/g). The resulting extract (OPVS-E) included gallic acid derivatives, hydrolysable tannins, flavonoids, fatty acids, and anacardic acids. Remarkably, OPVS-E displayed potent inhibitory activity against α-amylase (IC 50 = 2.05 μg/mL) and α-glucosidase (IC 50 = 41.07 μg/mL), by far more powerful than the anti-diabetic drug acarbose, OPVS-E exhibited a strong antiradical capacity against reactive oxygen species (ROS) without causing toxicity in intestinal cells (HT29-MTX and Caco-2). These findings introduce OPVS-E as a potential novel dual-action nutraceutical ingredient, able to mitigate postprandial hyperglycemia and counteract the ROS overproduction occurring in type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]