Designing CO oxidation catalysts for complex flue gases conditions is particularly challenging in fire scenarios. Traditional flue gas simulations use a few representative gases but often fail to adequately evaluate catalyst performance in real-world combustion conditions. In this study, we developed doping strategies using La and Cu to enhance the water resistance of Co3O4 catalysts. Catalyst 0.1La-Co3O4-CuO/CeO2 exhibits exceptional low-temperature catalytic activity, achieving 100% conversion at 130 °C. This enhancement is largely due to the introduction of La, which increases the active Co3+/Co2+ ratio and suppresses hydroxyl group formation on the Co3O4 surface. Cu doping also changes the Co3O4 lattice structure, forming Cu+ as active sites and enhancing the activity at low temperatures. For the first time, steady-state tube furnace and fixed bed were employed to evaluate the catalytic performance of CO in actual combustion atmosphere. Catalyst 0.1La-Co3O4-CuO/CeO2 maintains excellent catalytic efficiency (T100 = 120 °C) under well-ventilated conditions. However, its activity significantly decreases in poorly ventilated environments, due to the competitive adsorption of small molecules at active sites, such as acetone, commonly found in smoke. This study provides valuable insights for designing water-resistant, low-temperature, non-noble metal catalysts and offers a methodology for evaluating CO catalytic activity in real-world environments.