OBJECTIVE: The aim of this study was to explore the association between the expression of mitogen-activated protein kinase (MAPK)/extracellular regulated protein kinase (ERK) pathway and neuronal apoptosis in rats with white matter lesions (WML). MATERIALS AND METHODS: Sprague-Dawley (SD) rats were selected as the research objects. Rat models of ischemic WML were established by bilateral common carotid artery ligation. Subsequently, brain tissues were collected from rats in sham operation group and WML group, respectively. Hematoxylin-eosin (HE) staining assay was conducted to observe the pathological changes in white matters (WMs) (callosum, internal capsule, and optic nerve) and apoptotic cells in brain tissues. The protein expression levels of phosphorylated ERK (p-ERK) and ERK, phosphorylated MAPK (p-MAPK), and MAPK in tissues were measured by Western blotting. Immunohistochemistry was employed to detect the expression levels of p-ERK, ERK, p-MAPK, and MAPK in brain tissues of the two groups. Next, nerve cells were isolated from rats with WML as research objects. The phosphorylation of the MAPK/ERK pathway was suppressed using PD03259019 (a chemical drug, hereafter referred to as PD). Then, the changes in the protein expressions of apoptosis proteins B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) were determined before and after MAPK/ERK pathway inhibition. Meanwhile, changes in the messenger ribonucleic acid (mRNA) expression levels were detected via real-time fluorescent quantitative polymerase chain reaction (PCR), and changes in apoptosis were observed. RESULTS: HE staining revealed that in sham operation group, WMs had normal structure and intact morphology. The cells were regularly arranged, with little apoptosis of the nuclei in the center. However, there were abnormally arranged nerve cells, loose cortical structure, swollen cells, aberrant nuclear membrane, pyknosis, signs of cell degeneration and necrosis, apoptotic cells filled most of the field of vision, and relatively evident lesions in WML group. Besides, WML group exhibited significantly up-regulated expressions of p-ERK and p-MAPK, as well as basically unchanged expressions of ERK and MAPK (p<0.05). After PD was added for 1 d, 2 d, and 3 d, the MAPK/ERK pathway was repressed, which was the most significantly at 3 d. Furthermore, the anti-apoptotic phenotype of neurons was detected, which was more pronounced at 3 d (p<0.05). CONCLUSIONS: Rats with WML exhibited elevated MAPK/ERK activity and evident apoptosis. After inhibiting the phosphorylation site of MAPK/ERK in rat neuronal cells, the expression of pro-apoptotic protein decreased. and the apoptosis was relieved. In rats with WML, neuronal apoptosis is promoted by activating the MAPK/ERK pathway, thus worsening the condition.