Kidney fibrosis, a key feature of chronic kidney disease (CKD), is associated with oxidative stress and mitochondrial dysfunction. This review focuses on three pathways linking 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 medications such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, non-steroidal mineralocorticoid receptor antagonists (MRAs), and HIF-1α-prolyl hydroxylase inhibitors, which have shown reduced oxidative stress and collagen deposition in CKD. However, understanding the anti-fibrotic effects of these compounds in humans remains challenging due to practical and ethical difficulties in obtaining sequential kidney biopsies and the lack of specific fibrosis biomarkers. The review discusses the molecular and clinical scenarios of these pathways, their interconnections, and their role in oxidative stress and kidney fibrosis.Kidney fibrosis, a key feature of chronic kidney disease (CKD), is associated with oxidative stress and mitochondrial dysfunction. This review focuses on three pathways linking 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 medications such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, non-steroidal mineralocorticoid receptor antagonists (MRAs), and HIF-1α-prolyl hydroxylase inhibitors, which have shown reduced oxidative stress and collagen deposition in CKD. However, understanding the anti-fibrotic effects of these compounds in humans remains challenging due to practical and ethical difficulties in obtaining sequential kidney biopsies and the lack of specific fibrosis biomarkers. The review discusses the molecular and clinical scenarios of these pathways, their interconnections, and their role in oxidative stress and kidney fibrosis.