Artichoke by-products are a suitable source of health-promoting ingredients for the production of dietary supplements and food additives. A pressurized hot water extraction (PHWE) was developed to recover caffeoylquinic acids (CQAs) and flavone glycosides (FLs) from agro-industrial artichoke by-products. The main factors influencing PHWE efficiency and CQA isomerization (temperature, numbers of cycles, modifier, and extraction time) were carefully studied and optimized by response surface design. The proposed PHWE procedure provides an exhaustive extraction of CQAs and FLs (recoveries: 93-105% and 90-105%) from artichoke external bracts and leaves of different cultivars (p>0.05), without significant formation of artefacts generated by high temperatures. PHWE extracts showed CQA and FL levels (14-37 mg/g and 3-19mg/g, respectively) comparable to commercial products and marked antioxidative effects (EC50 11-83g/mL) by cellular antioxidant activity assay in human hepatocarcinoma HepG2 cells. These results proved that PHWE is an excellent green technique to recover bioactive compounds from artichoke agro-industrial residues.