Abstract: Renal fibrosis represents a common final pathway in the progression of various kidney diseases and markedly affects patients’ quality of life and clinical prognosis. In recent years, the interplay between mitochondria and inflammation has been recognized as one of the key drivers of fibrotic initiation and progression. This article systematically explores the central role of the mitochondrial– inflammation axis in the development of renal fibrosis and its potential molecular mechanisms, with a particular focus on the pro-inflammatory effects of mitochondrial damage– associated molecular pattern (mtDAMP) release and the bridging function of immune signaling pathways in the fibrotic process. By delineating the critical pathological events from stress stimuli to renal functional failure, this review further discusses current therapeutic strategies targeting this axis and highlights recent advances in their clinical translation. By integrating the latest research findings, this work aims to provide theoretical support and future research directions for a deeper understanding of the mechanisms underlying renal fibrosis and the development of targeted therapeutic strategies.