Orange peel (OP) is the main by-product from orange juice industry. OP is a known source of bioactive compounds and is widely studied for its antioxidant, anti-inflammatory, anti-cancer, anti-rheumatic, anti-diabetic and cardioprotective activities. Thus, this research focuses on the establishments of ultrasound-assisted extraction of phenolic compounds in orange peel using a sonotrode; objective framed in the European SHEALTHY (non-thermal physical technologies to preserve healthiness of fresh and minimally processed fruit and vegetables) project. For this purpose, a Box Behnken design of 27 experiments was carried out with 4 independent factors (ratio ethanol/water, time (min), amplitude (%) and cadence (%)). Quantitative analyses of TPC were performed by Folin method and the antioxidant activity was measured by ABTS and DPPH methods. The validity of the experimental design was confirmed by ANOVA and the optimal sonotrode extraction conditions were obtained by response surface methodology. The optimal extracts were characterized by HPLC coupled to mass spectrometer detectors. The highest phenolic content and antioxidant activity was obtained using 45/55 ethanol/water (v/v), 35 min, amplitude 90% (110 W) and cadence 100%. The established method allows the extraction of 30.42 mg/g dry weight of total phenolic compounds from OP; this value suppose an increment up to 60% higher than conventional extraction.