Objective To investigate the role of EGFR/STAT5 signaling pathway in the pathogenesis of rheumatoid arthritis (RA). Method Identifying the differentially expressed genes (DEGs) with bioinformatics analysis. Rheumatoid arthritis fibroblast-like synovial cells (RA-FLS) were collected from patients clinically and cultured in vitro. EGFR and STAT expression levels were detected in tissues using immunohistochemistry(IHC). Moreover the expression of downstream proteins of the EGFR/STAT5 pathway(IL-2, IL-15, Bcl-2, and Bcl-xL)were quantified in RA-FLS cells using western blot. Result It was found that EGFR expression was significantly different in RA synovium, and immunohistochemistry confirmed that EGFR and STAT5 was significantly expressed in RA synovium. Additionally, in vitro experiments using RA-FLS uncovered that protein expression levels of IL-2, IL-15, Bcl-2, and Bcl-xL were significantly increased compared to normal FLS. More importantly, the protein expression levels of IL-2, IL-15, Bcl-2, and Bcl-xL were significantly decreased after EGFR inhibitor use, while an opposite trend was observed when EGFR agonists were utilized. Conclusion Inhibiting EGFR/STAT5 signaling pathway results in the apoptosis of RA-FLS and prohibits the occurrence of RA-FLS inflammatory response, which can be used as a therapeutic target for RA.