Aqueous mixtures of glycerol and 2-hydroxypropyl-β-cyclodextrin (CD), two non-toxic eco-friendly substances, were used as a means of extracting antioxidant polyphenols from oak acorn (Quercur robur) husks. The process was optimized by implementing a central composite (Box-Behnken) experimental design and response surface methodology, taking into consideration the critical parameters (independent variables) of glycerol concentration (C gl ), CD concentration (C CD ) and temperature (T). The assessment of the extraction model was based on three responses: the total polyphenol yield (Y TP ), the antiradical activity (A AR ) and the reducing power (P R ). The model illustrated that Y TP depended significantly on C gl and C CD , but not on T, whereas both antioxidant properties considered (A AR and P R ) were temperature-dependent. The maximum predicted Y TP was 122.19 mg GAE per g dry husk weight, while the extract obtained under optimized conditions displayed strong antioxidant activity.