Propolis has given rise to refreshing interest in recent years in the field of conventional medicine. Its extraction represents an important process that requires optimal conditions, which strongly affect the yield of extraction, total polyphenols, flavonoid content, and radical scavenging capacity markers. The objective of the present study was to optimize the ultrasound-assisted extraction conditions of Moroccan propolis. The studied responses were the extraction yield, total polyphenols, flavonoid contents (TPC, TFC), and antioxidant activity of the extract evaluated by DPPH-IC50 and FRAP-EC50 assays. The response surface methodology (RSM) and specifically the Box–Behnken design (BBD) were used, taking into account three variables: sonication time (min), solvent/propolis ratio (mL/g), and ethanol concentration (%). After the realization of experiments and data analysis, optimal response values were 15.39%, 192 mg GAE/g of propolis,45.15 mg QEq/g, 29.8 µg/mL, and 128.3 µmol Fe2+/g for extraction yield, TPC, TFC, DPPH-IC50, and FRAP-EC50, respectively. Besides, optimal ultrasound extraction conditions were 15 min for sonication time, 30 mL/g for solvent/propolis ratio, and 40% for ethanol concentration. All obtained experimental values were in good agreement with the predicted values, suggesting that using an experimental design in the ultrasound-assisted extraction process and optimization was prudently chosen.