<p>Crocin, a major bioactive compound in saffron stigmas, is highly valued for its antioxidant properties and diverse applications in the pharmaceutical and food industries. An ultrasound-assisted extraction (UAE) method combined with natural deep eutectic solvents (NADES) was developed as a green and efficient approach. Besides, cryogenic grinding was introduced as an innovative pretreatment method, demonstrating superior performance in preserving the color, bioactive compounds, and antioxidant capacity of saffron compared to conventional grinding technique. Among the tested NADESs, choline chloride-sorbitol (ChCl-Sor, 1:1 mol/mol) showed the highest yield. The optimization of the UAE-NADES extraction variables, including particle size (0.1–0.3 mm), water content in NADES (10–50% w/w), ultrasonic power (80–200 W), and extraction time (1–30 min) was performed using response surface methodology (RSM) with central composite design (CCD). The optimal extraction variables were as follows: 0.1 mm particle size, 43.7% (w/w) water content in NADES, 200 W ultrasonic power, and the extraction time of 10 min. The predicted optimum values for crocin yield, total phenolic content (TPC), and antioxidant capacity (IC50) of saffron extract were 216.638 mg/g DW, 145.681 mg GAE/g DW, and 0.968 mg/mL, respectively. The optimum value for crocin yield was verified using HPLC analysis. Finally, the second-order kinetic model successfully showed the UAE process of crocin from saffron compared to the first-order model. This study highlights the combined potential of cryogenic grinding and UAE-NADES as efficient technologies for enhancing the extraction yield of bioactive compounds such as crocin and TPC with high antioxidant capacity from saffron stigmas.</p> Graphical Abstract <p></p>