The present study was conducted to optimize ultrasound-cellulase synergy extraction (UCSE) process of flavonoids from Astragali complanati Semen (ACS) adopting response surface methodology (RSM). The extraction efficiency of different extraction progress by UCSE under the 240W and 480W were compared, and the antioxidant activities were evaluated in vitro. The effects of five independent variables (cellulase addition, liquid-solid ratio, extraction time, extraction temperature, and ultrasonic power) on the extraction efficiency were explored, and four major factors (cellulase addition, liquid-solid ratio, extraction temperature and ultrasonic power) showing great influences were chosen to study their interactions by RSM. The relationships between ultrasound power 240W and 480W on substrates and cellulase were further explored by scanning electron microscopy and 3,5-dinitrosalicylic acid (DNS) method, respectively. The antioxidant activities on 1,1-diphenyl-2-picryl-hydrazyl radical (DPPH) and 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulphonate) radical (ABTS+) were evaluated in vitro. The optimal conditions: cellulase addition 930 U/g, liquid-solid ratio 24mL/g, extraction time 75min, extraction temperature 64°C and ultrasonic power 234W, under the adjusted conditions, the extraction rate was 1.937g/100g ACS. Ultrasound power 240W assisted extraction with cellulase improved the extraction efficiency of the antioxidant. From scanning electron microscopy, the substrate particles were finer and the pores were larger under the function of 240W, and the enzyme activity test further determined that 480W could reduce the effect of the cellulase. The UCSE extract exhibited great antioxidant activity in vitro, the IC50 of DPPH is 11.851µg/mL, and of ABTS+ is 23.426µg/mL.