Over the past decade, significant progress improved mitochondrial disorders diagnosis, but effective therapies remain lacking. A drug screening identified Ebselen (EBS) as enhancing oxidative phosphorylation-dependent growth in a yeast model of Barth syndrome, a cardiomyopathy caused by defective cardiolipin (CL) maturation, and in fungal models of other mitochondrial diseases involving defects in complex IV (CIV), mitochondrial DNA maintenance, mitochondrial translation, complex I (CI) and ATP synthase (CV), underlying Leigh syndrome, cytochrome c oxidase deficiency, hepatocerebral syndrome, MELAS, NARP and MILS. EBS also showed beneficial effects in human cells deficient in CL, CI, or CV, and in a CL-deficient mouse model. This organoselenium compound, known for its antioxidant and anti-inflammatory properties, is in phase III clinical trials for bipolar disorder and Meniere's disease. Our findings suggest that EBS’s rescuing activity is independent of inositol monophosphatase inhibition or antioxidant properties, which nonetheless support its potential use for these disorders. Our data reveal an undocumented mechanism of action that underlies the mitochondrial rescue induced by EBS. Its effect may involve (i) downregulation of cytosolic translation to restore proteostasis and (ii) pyruvate dehydrogenase complex-dependent stimulation of Krebs cycle to increase ATP yield, both potentially mTOR-dependent, as EBS accumulates in lysosomes. Thus, EBS holds promise as a therapeutic agent for Barth syndrome and a broader range of mitochondrial diseases.