Ultrasonic cell grinder extraction (UCGE), employing water as solvent, was proposed as a sustainable and efficient method for the extraction of two iridoid glycosides (morroniside and loganin) from Corni fructus. Extraction yields were determined by four variables: ratio of solution to solid, extraction power, extraction buffer time and extraction time. Data analysis by response surface methodology showed that best yields, 2.176% ± 0.006% (predicted value of 2.195%) for morroniside and 0.839% ± 0.004% (predicted value of 0.852%) for loganin, were obtained when the values of these four variables were set at 45:1 mL g−1, 1600 w, 2.3 s and 40 min, respectively. The yields of morroniside and loganin using UCGE method were 0.198–0.279% and 0.167–0.181% higher than that of traditional heat reflux extraction method, respectively. Thus, the UCGE method is more productive, economic and environmentally friendly and has great potential to be used widely in natural product chemistry.