Red raspberry seed was taken as main material in this study. The ultrasonic-cellulase assisted extraction on red raspberry seed flavonoids was optimized by response surface methodology. And changes of flavonoid content were investigated by establishing gastrointestinal model in vitro. Based on Box-Benhnken central combination design， extraction rate of flavonoids were taken as index， effects of three crucial factors were investigated by response surface experiment. The results showed that： optimum extraction conditions provided the maximum extraction rate（34.33 mg/g） of flavonoids were determined as follows： cellulase concentration was 0.009 mg/mL， ultrasonic extract power was 70 W， temperature was 55 ℃， pH was 5.5， volume fraction of ethanol was 60%， when the condition of solid-liquid ratio was 1 ∶ 40 g/mL. After the gastric digestion 2.5 h， quantity of flavonoids were 1.28 times higher than blank group. And after the digestion intestinal 2.5 h， quantity of flavonoids were 1.59 times higher than blank group. It indicates that both pepsin and trypsin could promote the release of red raspberry seed flavonoids.