Chronic cadmium (Cd) exposure causes severe adverse health effects on the human body, especially the kidney tissue. Studies have demonstrated oxidative stress to be involved in renal pathological variations after exposure to Cd, but few effective treatments are available for the disease yet. Therefore, the present study was carried out to investigate the potential therapeutic intervention and its underlying molecular mechanisms of melatonin (MT), a natural antioxidant with multiple biological activities, against renal injury caused by Cd exposure in mice. C57BL/6 male mice (eight-week-old) were intragastrically administered with CdCl, MT, or both for 30 days. Biochemical analysis showed that MT intervention significantly improved the SOD, GSH, and CAT activities while markedly decreasing the kidney MDA content of the mice exposed to Cd. Histological examination indicated that Cd exposure resulted in the atrophy of the renal glomerular, the degeneration and dilation of tubules, and the accumulation of fibrocytes. By contrast, MT administration effectively ameliorated the histological outcome of the injured kidney tissue. Moreover, administrating MT significantly inhibited proinflammatory cytokines TNF-α and iNOS expression in Cd-treated mice. Further, MT treatment markedly suppressed the expressions of renal fibrosis-related factors TGF-β1, α-SMA, and collagen Ⅰ in the injured renal tissue and the accumulation and development of renal fibrosis. In addition, the administration of MT significantly reduced the expression of caspase-3 and cell apoptotic death in the kidney tissue of Cd-exposed mice. In all, the data showed that MT has a compelling therapeutic potential in alleviating the pathological variations of renal injury caused by Cd exposure.