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Strategically positioned within the airspaces and lung parenchyma, resident macrophage populations act as first responders that sense epithelial and endothelial injury, initiate sterile inflammatory responses, and coordinate immune cell recruitment, thereby influencing whether injury resolves or progresses to chronic inflammation and fibrosis. Recent advances have revealed substantial heterogeneity and plasticity among lung macrophages shaped by developmental origin, anatomical niche, and local microenvironmental cues. Alveolar and interstitial macrophages engage in extensive bidirectional cross talk with epithelial and endothelial cells through cytokines, growth factors, and extracellular vesicles that collectively maintain pulmonary homeostasis and regulate responses to injury. In experimental models of vesicant, particulate, volatile organic compounds, microbial toxins, and toxic gas exposure, pulmonary macrophages undergo profound transcriptional, metabolic, and functional reprogramming. Early depletion of resident alveolar macrophages coupled with disproportionate recruitment of monocyte-derived macrophages has emerged as a conserved pathogenic feature of severe chemical-induced lung injury. This review summarizes current understanding of pulmonary macrophage ontogeny, functional specialization, and macrophage-epithelial cross talk during acute chemical inhalation injury, and discusses emerging therapeutic strategies aimed at modulating macrophage responses to restore pulmonary homeostasis. 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