Bleomycin (BLM)-induced pulmonary fibrosis is characterized by the inflammation in the alveoli and subsequent deposition of extracellular matrix (ECM), myofibroblasts and impaired fibrinolytic system. Here we describe major hematological changes, IL-17A mediated p53-fibrinolytic pathway and the high throughput hits of LC-MS analysis during the progression of pulmonary fibrosis and the therapeutic potential of curcumin against the disease progression. C57BL/6 mice were exposed to BLM, followed by the curcumin intervention after 24 and 48 h. Mice were sacrificed after 7 days to validate the hematology parameters, molecular pathways and proteomics. Various techniques such as western blot, immunofluorescence, RT-PCR, hematoxylin and eosin, Masson’s trichrome staining, and immunohistochemistry were used to validate the proposed theory. LC-MS analysis was done using Q-Orbitrap mass spectrometer. Schrödinger was used to perform the in silico molecular docking studies. BLM exposed mice exhibited the gradual weight loss and altered lung morphology, howevr, it was reversed by the curcumin treatment. The significant changes in the hematology parameters were confirmed the severity of BLM-exposure in the mice and IL-17A mediated p53-fibrinolytic system components expression and alveolar epithelial cells (AECs) apoptosis further confirmed the pathophysiology of pulmonary fibrosis. Differentially expressed proteins were characterized and mapped using proteomics approach. A strong interaction of curcumin is obsereved with p53, uPA, and PAI-I proteins. Key role of IL-17A mediated inflammation in the impairment of the p53-fibrinolytic system, and AECs apoptosis was confirmed during BLM-induced pulmonary fibrosis. Therapeutic efficacy of curcumin exhibited a protective role against the progression of pulmonary fibrosis, which promises the potent therapeutic modality to target IL-17A mediated p53-fibrinolytic system during pulmonary fibrosis.