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BACKGROUND RESULTS CONCLUSION In recent years, the demand for high‐quality natural extracts to be included in nutraceutical formulations has increased sharply. Hazelnut (Corylus avellana L.) shells (HZS) are underrated agricultural by‐products that could be exploited as a source of active ingredients with pro‐healthy properties. In the present study, a fully green microwave‐assisted extraction (MAE) method was established for the first time aiming to recover bioactive constituents from HZS with significant nutraceutical value. Key MAE parameters, including ethanol in water concentration, microwave power, irradiation time and solvent‐to‐powder ratio, were optimized through response surface methodology utilizing a Box–Behnken design to achieve the highest total phenolic content and antioxidant/antiradical activities in the final extract.The optimal MAE conditions (28% v/v ethanol/water, 270 s, 670 W, and 37 mL g−1) yielded an extract with significant scavenging capacity against reactive oxygen species and remarkable inhibitory activity towards both α‐amylase (IC50 = 7.73 μg mL−1) and α‐glucosidase (IC50 = 49.44 μg mL−1), demonstrating stronger hypoglycaemic properties than the anti‐diabetic drug acarbose. Additionally, fluorescence spectroscopy results highlighted the ability of the optimized extract from HZS (OHS‐E) to counteract advanced glycation end‐product formation throughout the glycation cascade in a dose‐dependent manner. Liquid chromatography/electrospray ionization‐tandem mass spectrometry profiling unveiled the presence of fatty acids and phenolic compounds, including lignans, flavonoids, gallic acid derivatives and diarylheptanoids. Lastly, the biocompatibility of OHS‐E was attested on HT29‐MTX and Caco‐2 intestinal cells.Altogether, these findings encourage the potential application of OHS‐E as an effective nutraceutical component against type 2 diabetes mellitus and oxidative stress. © 2024 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

[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]