Patients with idiopathic pulmonary fibrosis (IPF) often experience precipitous deteriorations, termed “acute exacerbations”(AE), marked by diffuse alveolitis and altered gas exchange, resulting in a significant loss of lung function or mortality. The missense isoleucine to threonine substitution at position 73 (I73T) in the alveolar type 2 cell-restricted surfactant protein-C (SP-C) gene (SFTPC) has been linked to clinical IPF. To better understand the sequence of events that impact AE-IPF, we leveraged a murine model of inducible SP-C I73T (SP-C I73T/I73T Flp+/−) expression. Following administration of tamoxifen to 8–12-wk-old mice, an upregulation of Sftpc I73T initiated a diffuse lung injury marked by increases in bronchoalveolar lavage fluid (BALF) protein and histochemical evidence of CD45+ and CD11b+ cell infiltrates. Flow cytometry of collagenase-digested lung cells revealed a transient, early reduction in SiglecF hi CD11b low CD64 hi CD11c hi macrophages, countered by the sequential accumulation of SiglecF lo CD11b+ CD64− CD11c− CCR2+ Ly6C+ immature macrophages (3 d), Ly6G+ neutrophils (7 d), and SiglecF hi CD11b hi CD11c lo eosinophils (2 wk). By mRNA analysis, BALF cells demonstrated a time-dependent phenotypic shift from a proinflammatory (3 d) to an anti-inflammatory/profibrotic activation state, along with serial elaboration of monocyte and eosinophil recruitment factors. The iv administration of clodronate effectively reduced total BALF cell numbers, CCR2+ immature macrophages, and eosinophil influx while improving survival. In contrast, resident macrophage depletion from the intratracheal delivery of clodronate liposomes enhanced Sftpc I73T-induced mortality. These results using Sftpc I73T mice provide a detailed ontogeny for AE-IPF driven by alveolar epithelial dysfunction that induces a polycellular inflammation initiated by the early influx of proinflammatory CCR2+ Ly6C hi immature macrophages.