Ultrasound (US) is being considered as a promising emerging advanced oxidation process to degrade persistent organic-pollutants. This paper investigated the effect of several operating parameters on the degradation of a recalcitrant pharmaceutical product, namely ibuprofen (IBP), using an ultrasound-assisted biological reactor. The tested operating parameters are the power density (960, 480) W/L, US frequency (1,142, 860, 578) kHz, working volume (500, 250) mL, initial IBP concentration (30, 60) mg/L, and pH (8.2, 4). It was observed that the IBP degradation was directly influenced by the power density, and the highest degradation efficiency (99%) was obtained at 960 w/L. However, the degradation of IBP at sonication time of 120 min was found to increase from 39% to 96% while decreasing the US frequency from 1,142 to 578 kHz. The working volume had no clear effect on the IBP degradation. The optimal pH was found to be 4, which resulted in 99.5% IBP degradation efficiency after 120 min of sonication time. The degradation of IBP followed the first order kinetics. Finally, the sonically-treated water was fed to a subsequent aerobic biological reactor. The results revealed that the remaining chemical oxygen demand (COD) after sonication was lowered in the biological reactor by a percentage of 47%.