Kidney fibrosis, a key feature of chronic kidney disease (CKD), is linked to oxidative stress and mitochondrial dysfunction. This review explores three pathways connecting oxidative stress and kidney fibrosis: hyperglycemia and mitochondrial energy imbalance, the mineralocorticoid signaling pathway, and the hypoxia-inducible factor (HIF) pathway. These pathways are targeted by drugs like SGLT2 inhibitors, non-steroidal mineralocorticoid receptor antagonists (MRAs), and HIF-1α prolyl hydroxylase inhibitors, which reduce oxidative stress and collagen deposition in CKD. However, understanding their anti-fibrotic effects in humans remains challenging due to ethical and practical difficulties in obtaining sequential kidney biopsies and the lack of specific fibrosis biomarkers in accessible matrices like urine. The review highlights the role of oxidative stress in kidney fibrosis, the mechanisms by which drugs target these pathways, and their potential in treating CKD. It also discusses the clinical evidence supporting the use of SGLT2 inhibitors, GLP-1 receptor agonists, and non-steroidal MRAs in reducing kidney fibrosis and improving outcomes in CKD patients. The review concludes that while there is promising evidence for these drugs, further research is needed to fully understand their anti-fibrotic effects in humans.Kidney fibrosis, a key feature of chronic kidney disease (CKD), is linked to oxidative stress and mitochondrial dysfunction. This review explores three pathways connecting oxidative stress and kidney fibrosis: hyperglycemia and mitochondrial energy imbalance, the mineralocorticoid signaling pathway, and the hypoxia-inducible factor (HIF) pathway. These pathways are targeted by drugs like SGLT2 inhibitors, non-steroidal mineralocorticoid receptor antagonists (MRAs), and HIF-1α prolyl hydroxylase inhibitors, which reduce oxidative stress and collagen deposition in CKD. However, understanding their anti-fibrotic effects in humans remains challenging due to ethical and practical difficulties in obtaining sequential kidney biopsies and the lack of specific fibrosis biomarkers in accessible matrices like urine. The review highlights the role of oxidative stress in kidney fibrosis, the mechanisms by which drugs target these pathways, and their potential in treating CKD. It also discusses the clinical evidence supporting the use of SGLT2 inhibitors, GLP-1 receptor agonists, and non-steroidal MRAs in reducing kidney fibrosis and improving outcomes in CKD patients. The review concludes that while there is promising evidence for these drugs, further research is needed to fully understand their anti-fibrotic effects in humans.