Powdered stone waste (PSW) obtained from a stone cutting industrial unit was applied as support for the immobilization of nano-sized ZnO to be utilized as an effective catalyst for the catalytic conversion of acetaminophen (ACE) under ultrasonication. The incorporation of ZnO nanostructures into PSW structure enhanced the specific surface area and pore volume of the as-prepared nanocompound. The change in the value of zero point of charge (pH) of the PSW after being covered also demonstrated the good immobilization and distribution of ZnO nanostructures on the surface of PSW. The sonocatalysis of ACE over ZnO/PSW followed pseudo-first order kinetic (reaction rate of 2.27 × 10 1/min). The highest degradation efficiency of 98.1% was attained when the ZnO/PSW-contained sono-reactor was irradiated by UVC light. The presence of t-butanol led to the lowest degradation efficiency (57.7%), indicating that the sonocatalytic conversion of ACE was hydroxyl radical (OH)-dependent. Although the mineralization efficiency of ACE by the process was not excellent, bio-toxicity assessment on the effluent revealed decreasing the inhibition percent from 50.8 to 16.7% within reaction time of 240 min.