Epithelial growth factor receptor (EGFR), a tyrosine kinase receptor, plays a critical role in lipopolysaccharide (LPS)-induced endotoxemia. Meanwhile, EGFR signaling is regulated by multiple feedback regulators, including mitogen-inducible gene 6 protein (Mig6). However, as an EGFR regulator, the role of Mig6 in endotoxemia is still remained unknown. Here, we reported for the first time that LPS treatment increased the expression of Mig6 and this effect could be inhibited by EGFR inhibitor, PD168393 or erlotinib. Furthermore, knocking down of Mig6 expression led to increased EGFR activation and inflammatory mediators (TNF-alpha, il-1beta) production in response to LPS treatment. On the other hand, the increased EGFR activation and TNF-alpha or il-1beta production in LPS treatment could be inhibited by Mig6 overexpression. Besides, in LPS-induced endotoxemia, ERK1/2 and p-38 activation required Mig6. All these results indicated that Mig6 regulates the production of inflammatory mediators (TNF-alpha, il-1beta) through inhibiting the over activation of EGFR, which in turn inhibit MAPKs signaling (ERK1/2, p-38). These finding suggested that Mig6 may be a novel potential target for controlling the over inflammatory response in endotoxemia.