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Background Atherosclerosis (AS) causes cardiovascular diseases such as myocardial infarction and myocardial fibrosis. Incidence of the population gradually increases with the aging of the global population. The inflammatory response is a key factor in myocardial fibrosis, and regular aerobic exercise can reduce inflammation and protect myocardial function. However, the protective mechanism of aerobic exercise against AS myocardial fibrosis is unclear. Objective To investigate the mechanism of the effect of aerobic exercise on myocardial fibrosis in AS mice. Methods From February to August 2022, twenty-seven 8-week-old male ApoE-/- mice were selected as the experimental subjects and randomly divided into the control group, model group and aerobic exercise group, with 9 mice in each group. The mouse model of AS was prepared, and the mice were trained with exercise. The myocardial tissue was observed by hematoxylin-eosin (HE) and Masson staining. The protein expressions of NOD receptor 3 (NLRP3), interleukin1β (IL-1β) and transforming growth factor β1 (TGF-β1) in myocardial tissue were detected by Western blotting. The expressions of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were detected. Results Masson staining results showed that myocardial fibrosis in the model group was significantly worse than that in the control group. Myocardial fibrosis in the aerobic exercise group was significantly improved compared with the model group. HE staining showed that myocardial cells in the model group were disorganized, with abnormal cell morphology and size, enlarged cell gaps and inflammatory cell infiltration. Cardiomyocytes of mice in the aerobic exercise group were still neatly arranged, with abnormal cell morphology and size, and the cell gap was basically normal. The expressions of NLRP3, IL-1β and TGF-β1 in the model group were higher than those in the control group, while the expressions of NLRP3, IL-1β and TGF-β1 in the aerobic exercise group were lower than those in the model group, and higher than the control group (P