In the present study, deep eutectic solvents (DESs) were prepared and firstly applied to extract flavonoids from Safflower using ultrasonic-assisted extraction (UAE), and DES2-UAE was selected as a green and efficient extraction method. The effects of extraction parameters on extraction efficiency (EE) of flavonoids were investigated by single-factor experiments and optimized using a Box-Behnken design (BBD). The optimal results were 56.37 mL/g liquid-solid ratio, 55.85 min extraction time, 41.44 °C extraction temperature and 188.55 W ultrasonic power, respectively. Under optimal extraction conditions, the highest EE of flavonoids (55.41 mg/g) was obtained. The verification experimental results were in good correlation with the predicted results. The adsorption and desorption experiments of flavonoids on five types of macroporous resins (NKA-2, AB-8, HPD-100, D-101 and S-8) were carried out, NKA-2 and S-8 showed higher adsorption/desorption capacities, successively followed by AB-8, D-101 and HPD-100. The adsorption behaviors were better explained by Langmuir isotherm model according to correlation coefficient on the basis of static adsorption test at different temperature. In conclusion, the developed DES2-UAE combined with macroporous resin enrichment can be an alternative method for the green and efficient extraction of bioactive flavonoids from plant materials.