Ionic liquid-based ultrasonic-assisted extraction as an effective method was first successfully developed at room temperature to extract aesculin and aesculetin from the traditional Chinese medicine Cortex fraxini. A series of 1-alkyl-3-methylimidazolium, with different cations and anions, were investigated and [C(4)mim]Br was selected as optimal solvent. Ultrasonic conditions including ionic liquid concentration, soaking time, ultrasonic power, ultrasonic time, ratio of liquid solid and the number of extraction cycles were discussed by single factor experiments and the main influence factors were optimized by response surface method in order to extract aesculin and aesculetin effectively from C. fraxini. The proposed approach was demonstrated as a higher efficiency, shorter extraction time and a new alternative for the extraction of aesculin and aesculetin from C. fraxini comparing with traditional reference extraction methods. No degradation of the target analytes had been observed at the optimum conditions as evidenced from the stability studies performed with standard aesculin and aesculetin. The proposed method also shows high reproducibility, which demonstrates ionic liquid-based ultrasonic-assisted extraction is a rapid, efficient and simple sample extraction technique. (C) 2011 Elsevier B.V. All rights reserved.