•Valorization of unexploited crop waste for obtaining of potent bio-compounds.•Development of fast microwave-assisted extraction of artichoke leaves antioxidants.•Performing of detailed two-level optimization of the process parameters.•Achievement of higher yields of stronger antioxidants than in competitive reports.•Obtaining of maximal yields of antioxidants in less than minute. This study has developed an improved and fast microwave-assisted procedure for extraction of high yields of natural antioxidants from artichoke leaves dust. The material is derived as an abundant residue remained after processing for the industrial tea blends preparation, having no commercial value. A key factors for optimization of the total polyphenolic (TPC) and flavonoid content (TFC) and antioxidant activities have been determined by using single factor experiments along with a response surface methodology. The optimal conditions for maximizing the combination of TPC/TFC and antioxidant activity were obtained as follows: ethanol concentration 67.81%, extraction time 50 s, liquid/solid ratio 41.78 mL/g, microwave power 180 W, whereas the corresponding responses resulted in: TPC − 205.59 ± 7.30 mg GAE/g dw, TFC − 79.75 ± 1.12 mg QE/g dw, and FRAP −1008.14 ± 37.15 mmolFe2+/g dw. Only 14.7 µg/mL of the extract concentration is required to inhibit 50% of DPPH free radicals. A comparative study confirmed that the proposed procedure yielded higher TPC, TFC and antioxidant activities than available extraction methods. It highlights a several fold reduced extraction time, caring an eco-friendly principle for obtaining of antioxidants from industrial, medicinal crop residues, which would be further easily valorized in food and pharmaceutical industry.