Metformin is a frontline hypoglycemic agent, which is mainly prescribed to manage type 2 diabetes mellitus with obesity. Emerging evidence suggests that metformin also exerts protective effects against various kidney diseases. Some postulate that kidney disease is actually a metabolic disease, accompanied by nonresolving pathophysiologic pathways controlling oxidative stress, endoplasmic reticulum stress, inflammation, lipotoxicity, fibrosis, and senescence, as well as insufficient host defense mechanisms such as AMP-activated protein kinase (AMPK) signaling and autophagy. Metformin may interfere with these pathways by orchestrating AMPK signaling and AMPK-independent pathways to protect the kidneys from injury. Furthermore, the United States Food and Drug Administration declared metformin is safe for patients with mild or moderate kidney impairment in 2016, assuaging some conservative attitudes about metformin management in patients with renal insufficiency and broadening the scope of research on the renal protective effects of metformin. This review focuses on the molecular mechanisms by which metformin imparts renal protection and its potential in the treatment of various kidney diseases.