This study investigates the degradation of a refractory emerging contaminant (i.e., ibuprofen) by a newly developed piezoelectric catalytic persulfate (PS) activation process. BaTiO3 nanoparticles (NP) and nanowires (NW) were hydrothermally synthesized and used as the piezo-catalysts to activate PS under ultrasonic irradiation for radical generation and ibuprofen (IBP) degradation. IBP was efficiently degraded in the US/BTO NW/PS system with a pseudo first order rate constant of 0.0818 min−1, and the rate constant was faster than that in the US/BTO NP/PS (0.0492 min−1), US/BTO NW (0.0324 min−1) and US/PS (0.0057 min−1) systems. The outstanding performance of IBP degradation in the US/BTO NW/PS system was attributed to the continuous generation of SO4− and OH via PS activation by the piezo-catalysis induced electrons. SO4− and OH contributed 53% and 44% to the IBP degradation respectively. Meanwhile, O2−, 1O2 and H2O2 were in-situ formed and identified as key intermediates for the generation of SO4− and OH. The IBP was partially mineralized and transformed to other organic compounds. The degradation products were identified using the UPLC/ESI-tqMS and a degradation pathway was proposed, which involved a sequence of hydroxylation, decarboxylation/demethylation and ring-opening reactions with SO4− and OH. This study demonstrates a new energy-saving approach to activating PS for micropollutant abatement and also provides insights into the mechanisms of the PS activation by the piezoelectric catalysis.