Chronic kidney disease (CKD) comprises a group of clinical syndromes affecting kidney structure and function, with various causes, high treatment costs, and a poor prognosis. Epigenetic modification of gene expression and cell function has been shown to play a key regulatory role in the occurrence and development of CKD. Homocysteine (Hcy) is a common amino acid-containing thiol group in the body. Hyperhomocysteinemia (HHcy) is a damaging condition involving many organs, and is an independent predictor of end-stage renal disease morbidity and mortality. This review considers the relationship between HHcy and chronic renal injury, and examines research progress in the role of epigenetic modification in the mechanism of Hcy-mediated chronic renal injury, with the aim of furthering our understanding of the occurrence and development of CKD. This process and its mechanism provide new ideas and a theoretical basis for further research into CKD.