<p>Pulmonary infections are common respiratory diseases caused by a variety of pathogens, some of which can lead to epidemics. When they progress to acute lung injury or acute respiratory distress syndrome, the mortality rate is high and effective treatment options are lacking. Macrophages play a crucial role in the development and progression of lung injury, and serve as core components of immune regulation in the lungs. Therefore, regulation of macrophages to intervene in the progression of infection-induced lung injury is a promising research direction. However, the existence of different macrophage subsets and their inherent heterogeneity has led to the failure of many studies to achieve effective results, thereby limiting their clinical applications. We believe that interventions targeting macrophages must consider factors, such as macrophage subsets, timing of interventions, patients’ varying immune states, and clinical stages, rather than simply focusing on regulating their phenotypes. This distinction is the key to the success of macrophage-targeted therapies. In this review, we summarize the characteristics of two distinct macrophage subpopulations, lung-tissue-resident alveolar macrophages and monocyte-derived macrophages, along with intervention strategies and research progress at various time points, with the aim of providing insights and directions for future research.</p>