Abstract: Perovskite oxides have shown great potential for the catalytic oxidation of multiple pollutants in flue gas because of their stable structures, tunable compositions, and excellent redox properties. However, pristine perovskites often suffer from insufficient oxygen mobility and limited active sites, which can be effectively addressed by defect engineering. Unlike previous reviews that mainly focus on single-pollutant removal or single-defect engineering, this review focuses on the synergistic catalytic oxidation of multiple pollutants over defect-engineered perovskites, with particular emphasis on multi-defect coupling strategies and poisoning resistance under realistic flue gas conditions. Accordingly, this article systematically reviews synthesis strategies for defect-engineered perovskite oxides, with an emphasis on structural regulation and performance optimization, including A/B-site metal doping, O-site non-metal doping, surface etching/reconstruction, and urea-assisted non-stoichiometric regulation. Based on a critical review of the literature, we propose that single-defect regulation is insufficient to address the competitive adsorption and synergistic conversion among multiple pollutants; instead, the coordinated activation of oxygen vacancies and lattice oxygen is crucial for improving multi-pollutant catalytic efficiency. These findings suggest that optimizing a single defect type alone cannot universally enhance catalytic performance, highlighting the need for multi-defect coupling. For instance, a dual-defect 2U-La_0.8MnO₃ perovskite achieves 97.6% NO oxidation efficiency at 210 °C with nearly 100% conversion to NO₂, and achieves 100% Hg⁰ removal over a wide temperature range of 40–250 °C with an adsorption capacity of 23.86 mg/g, outperforming most reported transition metal oxide catalysts. Furthermore, existing studies predominantly focus on single-defect regulation and single pollutant removal, resulting in a limited understanding of the synergistic oxidation mechanisms of multiple pollutants in complex flue gas systems. Under practical operating conditions, these catalysts are susceptible to poisoning by components such as SO₂ and H₂O, leading to reduced activity and poor stability. Specifically, SO₂ tends to form stable sulfates on active sites, while H₂O competes for adsorption sites and may hydrolyze surface species; both effects severely limit long-term operation. To overcome these bottlenecks, future research should focus on: (i) transitioning from single-defect to multi-defect coupling to construct complex active structures; (ii) introducing machine learning-assisted design to rapidly screen optimal defect combinations; (iii) systematically investigating the competitive adsorption and synergistic reaction mechanisms of multiple pollutants using in situ/operando characterization; and (iv) enhancing catalyst resistance to SO₂ and H₂O poisoning through surface modification and interface engineering, thereby achieving efficient and stable synergistic control of multiple pollutants in flue gas.