The extraction of Castanea sativa leaves (CsLs) with selected solvents (96% ethanol, methanol and acidified water) was assessed by means of a set of experiments following a Box–Wilson central composite circumscribed (CCC) design. CsL extraction was assessed on the basis of experimental results determined for the yield in soluble compounds, the yield in phenolics and the antioxidant activity of extracts. The in vitro antioxidant activity was measured in terms of the scavenging abilities for α,α-diphenyl-β-picrylhydrazyl (DPPH) radical. Selected extracts were also assayed for scavenging activity against reactive oxygen species (ROSs) and reactive nitrogen species (RNSs). The highest extraction yields were obtained using methanol, whereas water allowed a selective extraction (with yields in phenolics up to 9 mg Gallic Acid Equivalent/100 mg CsL) and provided the most concentrated (54 mg GAE/100 mg solid) and active extracts. The major compounds identified in extracts were gallic acid, protocatechuic acid, 4-hydroxybenzoic acid, vanillic acid, rutin, quercetin and apigenin.