Oxygen vacancies (V O ) constructing in metallic compounds have been verified to enhance hydrogen peroxide (H 2 O 2 ) activation for pollutants treatment. However, the interactions between surface V O concentration and H 2 O 2 were still ambiguous. In this study, perovskites with different surface V O concentration were successfully prepared by a simple sol-gel process. Experimental results showed that A-site cation deficient was capable of distorting FeO 6 octahedra in Ca 1−x FeO 3-δ (x = 0, 0.1, 0.2) orthorhombic perovskites for the regulation of surface V O concentration. Afterwards, Ca 0.9 FeO 3-δ exhibited excellent catalytic activity and stability for tetracycline (TC) degradation, which was 4 times higher of catalytic enhancement than that of the raw Ca 1.0 FeO 3-δ . Moreover, up to 9, 17 and 27 times of catalytic enhancement as compared with commercial Fe 3 O 4 , ɑ-FeOOH and Fe 2 O 3 towards TC degradation. Based on electron spin resonance and free radical quenching experiments, the hydroxyl radical (∙OH) was the main active species for the catalytic degradation of TC. Meanwhile, higher or lower surface V O concentration was harmful to the production of ∙OH. Additionally, the toxicity of TC degradation by-products exhibited a decreasing trend according to the results of toxicological simulation. This work provides a new strategy for designing an efficient and promising heterogeneous Fenton-likes catalyst for environmental remediation. • Perovskite with abundant surface V O was synthesized by sol-gel method. • Surface V O concentration was regulated by regulated the A-site cation deficient. • Higher or lower surface V O concentration was hamful to the activation of H 2 O 2 . • Degradation intermediates were identified, and possible pathways were proposed.