As a chronic inflammatory disease, atherosclerosis can affect the occurrence of skeletal muscle autophagy through a variety of mechanisms. Previous studies have demonstrated that exercise enhances autophagic activity through irisin-mediated pathways. Building upon this evidence, this study investigated the effects of a 12-week aerobic exercise training on irisin levels and skeletal muscle autophagy-related proteins in atherosclerotic mice. Male C57BL/6J and mice were randomly assigned to four groups: Control Group (C), Aerobic Exercise Group (CE), Control Group (AC), and Aerobic Exercise Group (AE). Serum and muscle irisin levels were measured by ELISA; the expression levels of FNDC5, AMPK/mTOR pathway proteins and autophagy markers were detected by immunoblots, and muscle morphology was examined using H&E staining. Compared with the C group, the serum levels of TAG, TC, and LDL-C were higher than the AC group. Aerobic exercise increased irisin levels in skeletal muscle, upregulated the expression of LKB1 and p-AMPK, and presented an elevated LC3-II/I ratio, accompanied by reduced mTORC1 expression in CE mice. Aerobic exercise increased FNDC5 expression and irisin levels in serum and skeletal muscle, but also upregulated mTORC1 expression and reduced the LC3-II/I ratio in the AE group. Aerobic exercise enhances irisin synthesis and improves dyslipidemia in mice. However, the increased expression of the mTORC1 protein contributed to decreasing the expression of autophagy-related proteins following exercise.