This study establishes critical role for Drp1 hyperactivation and its interaction with a single mitochondrial outer membrane adaptor, Fis1, as a driving force behind mitochondrial dysfunction in ALS. Specific Drp1/Fis1 inhibitors, such as P110, that help restore mitochondrial dynamics without affecting the basal mitochondrial fission, may provide novel disease‐modifying treatment approach. Further, this therapeutic approach might be useful in other types of muscular dystrophy with dysfunctional or aberrant mitochondrial dynamics.