Our laboratory developed a peptide inhibitor, P110, that blocks the increased Drp1 association with mitochondria by selectively inhibiting Drp1/Fis1 interaction under pathological conditions. Mitochondrial dysfunction was evident in fibroblasts of ALS patients carrying pathogenic mutations in SOD1 (I113T), in FUS1 (fused in sarcoma; R521G), or in TDP43 (TAR DNA‐binding protein 43; G289S) genes and was associated with an increased Drp1 association with the mitochondria. Further, expression of SOD1 G93A in motor neurons affected a range of signaling pathways. Correcting mitochondrial dysfunction by inhibition of pathological fission induced by Drp1/Fis1 interaction using P110 had a beneficial effect. Finally, therapeutic administration of P110 suppressed muscle atrophy and mitochondrial structural defects and enhanced motor activity and life span in SOD1‐G93A ALS mouse model.