The occurrence and development of silicosis is related to the interaction of multiple cells through signal transmission caused by silica dust. Including inflammatory changes reduced by macrophages and phenotypic transdifferentiation reduced by lung fibroblasts. As a communication medium between cells, exosomes have become a hot research topic. To explore the role of exosomal proteins in the occurrence and development of silicosis and the possible intervention targets, this study conducted proteomic analysis of macrophage-derived exosomes induced by silica, to identify specific proteins for intervention. In this study, we used proteomic analysis to screen exosomal protein profiles from the RAW264.7 macrophages exposed to silica. A total of 291 proteins were differentially expressed, of which 178 were upregulated and 113 were downregulated. By performing functional annotation and analysis of the differentially expressed proteins, we identified proteins SPP1, HMGB3, and HNRNPAB, which were consistent with the proteomics analysis. The involvement of SPP1 protein in fibrosis was studied further. Knocking down the expression of SPP1 in exosomes resulted in a decrease in fibrosis-related indicators. These results help to understand that exosomal protein can mediate cell communication and play a key role in the transition from fibroblasts to myofibroblasts. Further, this study also provided strategies and scientific basis for future studies on the intervention of silicosis.