AbstractCatalysis is vitally important for chemical engineering, energy, and environment. It is critical to discover new mechanisms for efficient catalysis. For piezoelectric/pyroelectric/ferroelectric materials that have a non‐centrosymmetric structure, interfacial polarization‐induced redox reactions at surfaces leads to advanced mechanocatalysis. Here, the first flexocatalysis for 2D centrosymmetric semiconductors, such as MnO₂ nanosheets, is demonstrated largely expanding the polarization‐based‐mechanocatalysis to 2D centrosymmetric materials. Under ultrasonic excitation, the reactive species are created due to the strain‐gradient‐induced flexoelectric polarization in MnO₂ nanosheets composed nanoflowers. The organic pollutants (Methylene Blue et al.) can be effectively degraded within 5 min; the performance of the flexocatalysis is comparable to that of state‐of‐the‐art piezocatalysis, with excellent stability and reproducibility. Moreover, the factors related to flexocatalysis such as material morphology, adsorption, mechanical vibration intensity, and temperature are explored, which give deep insights into the mechanocatalysis. This study opens the field of flexoelectric effect‐based mechanochemistry in 2D centrosymmetric semiconductors.