Background <p>Fibrosis is a pathological process characterized by excessive extracellular matrix deposition, leading to tissue stiffening and organ dysfunction, posing a significant threat to human health. In recent years, histone methylation, a key epigenetic modification, has been increasingly recognized for its crucial regulatory role in the initiation and progression of fibrosis. By modulating chromatin structure and gene expression, histone methylation influences the activation of fibrosis-related cells, inflammatory responses, and cellular fate transitions.</p> Main body <p>This review systematically summarizes the molecular mechanisms of histone methylation in fibrosis across multiple organs, including the kidney, liver, heart, and lungs. It emphasizes the functions and regulatory networks of methyltransferases and demethylases, integrating the latest experimental and clinical findings. Furthermore, potential therapeutic strategies targeting histone methylation are discussed, highlighting their promise for precise anti-fibrotic interventions.</p> Conclusions <p>By consolidating advances in multi-organ fibrosis research, this article aims to provide a theoretical foundation and practical guidance for the future development of targeted fibrosis therapies.</p>