The main purpose of the present study is to predict the optimal values of the ultrasound-extraction conditions by employing the response surface method based on Box-Behnken design from Moringa oleifera leaves. The impact of three independent variables, namely the extraction time (5,15, and 25 min), solid to the solvent ratio (60%, 70%, and 80%), and ultrasonic amplitude (20%, 60%, and 100%) on the extraction yield and total phenolic/flavonoid content were studied. Analysis of variance (ANOVA) was employed to estimate the significance of the independent parameters and the model. An extraction time of 15 min, an ultrasonic amplitude of 100%, and a solid to solvent ratio of 80% were found to be optimal values. The findings of this investigation revealed that at optimal independent factors, the values of the extraction yield, total flavonoids, and phenolics content were found to be 83.75 mgL −1 ,50 mgL −1 , and 0.974 g, respectively. The obtained results indicated that BBD-RSM design could effectively be used in the optimization of the ultrasonic-assisted extraction process. To the best of our knowledge, this is the first study assessing the effect of US power, time of extraction, and solid to the solvent ratio on the extraction yield and phenolics content/flavonoids content of Moringa oleifera leaves cultivated in Iran.