Objective To optimize the extraction process of total flavonoids from pomelo peel by natural deep eutectic solvents (NADES) combined with microwaves.Methods The extraction ability of flavonoids from pomelo peel is analyzed among three NADES and conventional extractants combined with microwaves. Additionally, the extraction process is optimized by response surface experiment, and the antioxidant activity of the extracts is evaluated.Results The optimal total flavonoid extraction rate is 2.20 percent at a liquid-solid ratio of 23∶1 (mL/g), a water content of 29%, an extraction temperature of 73 ℃, and a microwave time of 40 seconds. Under these conditions, the DPPH and hydroxyl radical scavenging rate are 93.32% and 87.15%, the reducing power is 0.57, the metal ion chelation rate is 54.92%, and the lipid peroxidation inhibition rate is 29.78%.Conclusion A high extraction rate of flavonoids from pomelo peel is achieved by NADES combined with microwaves, with the resulting flavonoids exhibiting strong in vitro antioxidant activity.