Silicosis is a fibrotic disease caused by prolonged inhalation of silica particles. Signal regulatory protein alpha (SIRPα) and its ligand CD47, key innate immune checkpoints mediating inhibition of phagocytosis, have been reported to regulate organ fibrosis. However, the role of SIRPα/CD47 in silicosis remains unexplored. In this study, a silicosis mouse model was constructed and revealed a significant upregulation of SIRPα and CD47 expression in lung tissue with disease progression. In addition, the expression patterns of SIRPα and CD47 in various silicosis effector cells exhibit distinct cell specificity. Using RRx-001 to block SIRPα/CD47 signaling in mice, we observed a marked reduction in lung injury, decreased collagen deposition, and improved pulmonary function. Mechanistically, blocking SIRPα/CD47 affected T cell activation, macrophage polarization and the expression of pro-inflammatory and pro-fibrotic factors. In vitro, we found that inhibiting SIRPα/CD47 countered the silica-induced suppression of macrophage phagocytosis and induced macrophage polarization towards the M1 phenotype. Additionally, levels of soluble SIRPα and CD47 in the peripheral blood of silicosis patients were significantly higher than those in healthy controls. In summary, this study demonstrates that SIRPα/CD47-mediated immunomodulatory signaling is the driving factor for the progression of silicosis, and this pathway might serve as a therapeutic target for silicosis treatment.