Chronic kidney disease (CKD) is characterized by persistent inflammation and progressive fibrosis, ultimately leading to end-stage renal disease. Although many studies have investigated the factors involved in the progressive deterioration of renal function, current therapeutic strategies only delay disease progression, leaving an unmet need for effective therapeutic interventions that target the cause behind the inflammatory process and could slow down or reverse the development and progression of CKD. Epidermal growth factor receptor (EGFR) (ERBB1), a membrane tyrosine kinase receptor expressed in the kidney, is activated after renal damage, and preclinical studies have evidenced its potential as a therapeutic target in CKD therapy. To date, seven official EGFR ligands have been described, including epidermal growth factor (EGF) (canonical ligand), transforming growth factor- α, heparin-binding epidermal growth factor, amphiregulin, betacellulin, epiregulin, and epigen. Recently, the connective tissue growth factor (CTGF/CCN2) has been described as a novel EGFR ligand. The direct activation of EGFR by its ligands can exert different cellular responses, depending on the specific ligand, tissue, and pathological condition. Among all EGFR ligands, CTGF/CCN2 is of special relevance in CKD. This growth factor, by binding to EGFR and downstream signaling pathway activation, regulates renal inflammation, cell growth, and fibrosis. EGFR can also be “transactivated” by extracellular stimuli, including several key factors involved in renal disease, such as angiotensin II, transforming growth factor beta (TGFB), and other cytokines, including members of the tumor necrosis factor superfamily, showing another important mechanism involved in renal pathology. The aim of this review is to summarize the contribution of EGFR pathway activation in experimental kidney damage, with special attention to the regulation of the inflammatory response and the role of some EGFR ligands in this process. Better insights in EGFR signaling in renal disease could improve our current knowledge of renal pathology contributing to therapeutic strategies for CKD development and progression.