Per‐ and polyfluoroalkyl substances (PFAS) pose significant environmental and health risks due to their ubiquitous presence and persistence in water systems. Herein, the efficacy of piezocatalysis using barium titanate nanoparticles under ultrasound irradiation for the degradation and defluorination of perfluorooctane sulfonate (PFOS) in water is investigated. The research demonstrates a substantial 90.5% degradation and 29% defluorination of PFOS after 6 h of treatment, highlighting the potential of piezocatalysis as a promising approach for PFAS degradation. Additionally, the quantification of degradation products elucidates the transformation pathways of PFOS, suggesting a stepwise chain‐shortening mechanism. The findings underscore the importance of continued research in optimizing piezocatalytic processes and exploring synergistic approaches with other advanced oxidation methods to effectively address PFAS contamination challenges. These efforts are essential for advancing sustainable water treatment strategies and mitigating the environmental and health hazards associated with PFAS contamination.