Mitochondrial dysfunctions are associated with pathogenesis of various brain disorders, including Alzheimer’s, Parkinson’s and Huntington’s diseases, amyotrophic lateral sclerosis, Leigh syndrome, and autism spectrum disorder. For studying mitochondrial dysfunction, as well as developing and testing new therapeutic strategies, in vivo studies on zebrafish (Danio rerio) are of particular interest due to their biological characteristics, practical laboratory maintenance, and high throughput. Here, we address genetic and pharmacological models of common mitochondrial dysfunctions and related neurological disorders in rodents and zebrafish, focusing of the growing utility of these fish in modeling mitochondrial pathogenesis of various CNS diseases.