Ultrasound and microwave-assisted extraction (UMAE) technique was used to extract flavones from Vaccinium bracteatum Thunb. leaves (VBTL). Mathematical model based on Fick’s law was established to investigate the extraction process. In order to validate the model developed under various operating conditions, effect of microwave power, temperature and solid–solvent ratio on model and yield was investigated. Values of effective diffusion coefficient were calculated based on the mathematical model. Moreover, Biot number (Bi) was employed to validate the assumptions in mathematical modeling and understand the mechanism of extraction. The results indicated that the values of effective diffusion coefficient were in the range from 3.474 × 10−11 to 10.019 × 10−11 m2/s, and the activation energy (Ea) was obtained as 47.74 kJ/mol. Values of Bi suggested the extraction process was controlled by diffusion. Our developed mathematical model gave a good approximation of experimental data under various operating conditions and could be used for further process design and investigation on extraction of flavones from VBTL.