Objective: To investigate the role and mechanism of transthyretin (TTR) in the white matter lesion (WML) model of hypertensive rats. Methods: Spontaneously hypertensive rats were randomly divided into sham group, model group, empty vector group and TTR overexpression group. The empty vector group and the TTR overexpression group were respectively injected with empty vector lentivirus and TTR overexpression lentivirus in the bilateral ventricles. One week after lentivirus injection, the WML model was established by bilateral common carotid artery occlusion. Three weeks after modeling, new object recognition experiments were conducted and the resolution index was calculated. The degree of demyelination of the corpus callosum was observed by firm blue staining, the degree of neuronal damage of the corpus callosum was observed by hematoxylin-eosin staining and Nysl staining, the mitochondrial structure in the corpus callosum was observed by transmission electron microscopy. The expression levels of myelin proteins such as basic myelin protein (MBP), neurofilament protein 200 (NF200) and mitochondrial autophagy proteins PTEN-induced kinase 1 (PINK1), parkin, and microtubule-associated protein 1 light chain 3beta (LC3B) in the corpus callosum were detected by western blot. The levels of oxidative stress indicators malondialdehyde (MDA) and superoxide dismutase (SOD) in the corpus callosum were detected by the kit. Results: ① In the TTR overexpression group, cognitive function decline and pathological damage of the corpus callosum were alleviated, the resolution index increased, firm blue staining enhanced, neuronal morphology improved, and Nissl bodies increased; ② The expression levels of MBP and NF200 in the corpus callosum increased in the TTR overexpression group. ③In the TTR overexpression group, mitochondrial damage was alleviated, the number of mitochondrial cavities decreased, mitochondrial cristae were visible, the expression levels of PINK1, parkin, LC3B and the level of MDA decreased, and the level of SOD increased. Conclusion: TTR improves WML in spontaneously hypertensive rats, alleviates cognitive decline, demyelination and neuronal loss in corpus callosum, and reduces mitochondrial damage.The possible molecular mechanism related to the above-mentioned neuroprotective effects of TTR is reducing mitochondrial damage.