In this study, the ultrasound-assisted extraction (UAE) of flavonoids with maximal antioxidant and tyrosinase inhibitory activities and identification of the principal individual flavonoids compounds of Semen Oroxyli by UHPLC-DAD-QTOF-MS/MS was proposed. The method was optimized by a three-factor-three-level Box–Behnken design (BBD) and Derringer’s desirability function using methanol concentration, extraction time, and liquid/solid ratio as factors, while, the total flavonoids content (TFC), antioxidant activities (DPPH, ABTS, FRAP, superoxide anion and hydroxyl radicals) and tyrosinase inhibitory activity as responses. The experimental results showed that the optimal extraction conditions were as followed: a solvent of 69.90% methanol, an extraction time of 30.64 min and a liquid/solid ratio of 31.30 mL/g, which give individual response values of 19.79 mg RE/g, 78.66%, 99.92%, 19.05 mM FE/g, 20.49%, and 13.37% for TFC, DPPH, ABTS, FRAP, superoxide anion and hydroxyl radicals, respectively. In addition, the tyrosinase inhibition assay showed that the extract of Semen Oroxyli exhibited strong inhibitory activity against the tyrosinase. There were no significant differences between the results of the optimization experiments and those predicted by the models. By UHPLC-DAD-QTOF-MS/MS analysis, the main flavonoids identified in the optimized UAE extracts of Semen Oroxyli were oroxin B, oroxin A, chrysin-7-O-β- d-glucuronid, baicalein and chrysin.