Traditional anthraquinone method for producing H2O2 needs high energy consumption and substantial toxic by-production release. Recently, piezocatalysis that can conquer the above shortcomings emerges as a promising catalytic technique and arouses considerable interests. With rare application of piezocatalysis on H2O2 generation, exploiting efficient tactics for improving piezocatalytic H2O2 productivity is highly anticipated. Herein, atomic-level thickness Bi4Ti3O12 nanosheets with rich surface oxygen vacancies (OVs) are prepared for two-step single-electron O2 reduction into H2O2. Piezoelectric force microscopy, piezo-electrochemical tests, and Finite Element Simulation disclose that both the atomic-level thickness and OVs enlarge the piezoelectric coefficient, rendering stronger piezoelectric polarization for accelerating the charge separation and reaction kinetics. Density functional theory calculations uncover that the surface OVs also decrease the adsorption energy of O2 molecules for facilitating their activation. The ultra-thin Bi4Ti3O12 with optimal OVs content shows a piezocatalytic H2O2 evolution rate of 1611.2 μmol·h−1·g−1 with benign durability. This work delivers a joint-strategy for advancing the piezocatalytic activity, and furnishes a reference for producing useful chemicals by harvesting and utilizing accessible vibrational energy.