Chronic kidney disease (CKD) is commonly characterized by proteinuria and leads to progressive glomerulosclerosis and tubulointerstitial fibrosis. Accumulating evidence implicates mitochondrial dysfunction including reactive oxygen species (ROS) overproduction in the pathogenesis of CKD. Mitochondrial function and ROS production are regulated by mitochondrial uncoupling. Niclosamide ethanolamine salt (NEN) is a mild mitochondrial uncoupler, which reduces urinary albumin excretion in mice with diabetic kidney disease. However, its role in nondiabetic kidney disease has not been investigated. Here we show that NEN exerts renoprotective effects in adriamycin induced nondiabetic kidney disease. It reduces urinary protein excretion, restores podocyte function, ameliorates renal pathological injury, and decreases the excretion of the urinary tubular injury biomarkers NGAL and Kim-1. Specifically, NEN uncouples isolated kidney mitochondria, and dose-dependently decreases the renal production and urinary excretion of H2O2. Moreover, NEN increases catalase and PGC-1α expression, which might accelerate H2O2 scavenging. The results of this study provide the first evidence that NEN protects kidney in nondiabetic kidney disease by regulating redox balance.