Post-stroke cognitive impairment (PSCI) is a common complication of strokes and is associated with the demyelination of nerve fibers. AMX0035, a drug currently used to treat motor neuron diseases, may aid in preventing oligodendrocyte apoptosis and alleviating demyelination by targeting the pathways involved in ERS and mitochondrial dysfunction. All animals were randomly divided into four groups: the sham, sham+AMX0035, middle cerebral artery occlusion (MCAO), and MCAO+AMX0035 group. The Morris water maze was used to test cognitive function, and changes in myelin structure in the brain were investigated using transmission electron microscopy (TEM), Luxol fast blue (LFB) staining, and myelin basic protein (MBP) immunofluorescence staining. Western blot was performed to detect proteins associated with ER stress and mitochondrial dysfunction, and double-labeling immunofluorescence was utilized to localize oligodendrocytes and apoptosis-related proteins. Neurological function scores and TTC staining confirmed the successful establishment of the MCAO rat model. The Morris water maze experiment revealed impaired cognitive function in MCAO rats, which significantly improved following the AMX0035 intervention. TEM and LFB staining showed the disrupted myelin structure in the MCAO group, while AMX0035 effectively ameliorated this myelin damage. Immunofluorescence examination and Western blot revealed the decreased expression of MBP in MCAO rats, increasing with AMX0035 treatment. TUNEL staining demonstrated increased cell apoptosis in MCAO rats, which was reduced following AMX0035 therapy. Western blot detected significant increases in proteins associated with the ER stress pathway and proteins linked to mitochondrial dysfunction in the MCAO group, all of which were downregulated after AMX0035 intervention. Double-labeling immunofluorescence staining revealed a significant increase in the number of cytochrome c and caspase 12 oligodendrocyte cells in MCAO rats, which decreased after AMX0035 administration. The activation of ER stress and mitochondrial dysfunction pathways following MCAO led to oligodendrocyte damage and apoptosis. AMX0035 can inhibit these pathways, reduce oligodendrocyte apoptosis, and alleviate demyelination, thereby improving PSCI.