Nephrotic syndrome (NS), a frequent chronic kidney disease in children and young adults, is the most common phenotype associated with primary coenzyme Q (CoQ) deficiency and is very responsive to CoQ supplementation, although the pathomechanism is not clear. Here, using a mouse model of CoQ deficiency-associated NS, we show that long-term oral CoQ supplementation prevents kidney failure by rescuing defects of sulfides oxidation and ameliorating oxidative stress, despite only incomplete normalization of kidney CoQ levels and lack of rescue of CoQ-dependent respiratory enzymes activities. Liver and kidney lipidomics, and urine metabolomics analyses, did not show CoQ metabolites. To further demonstrate that sulfides metabolism defects cause oxidative stress in CoQ deficiency, we show that silencing of sulfide quinone oxido-reductase (SQOR) in wild-type HeLa cells leads to similar increases of reactive oxygen species (ROS) observed in HeLa cells depleted of the CoQ biosynthesis regulatory protein COQ8A. While CoQ supplementation of COQ8A depleted cells decreases ROS and increases SQOR protein levels, knock-down of SQOR prevents CoQ antioxidant effects. We conclude that kidney failure in CoQ deficiency-associated NS is caused by oxidative stress mediated by impaired sulfides oxidation and propose that CoQ supplementation does not significantly increase the kidney pool of CoQ bound to the respiratory supercomplexes, but rather enhances the free pool of CoQ, which stabilizes SQOR protein levels rescuing oxidative stress.