Objective: To observe the effects of moxibustion or moxa smoke on serum lipids, aorta and liver pathology, and carotid plaque stability in atherosclerosis. Methods: Fifty-four 8-week-old ApoE−/- mice were randomly divided into three groups (untreated, moxibustion, and moxa smoke) and received a high-fat diet. Eighteen wild-type C57BL/6 mice of the same age were used as controls. The intervention (none, moxibustion between the nipples, or 10–15 mg/m3 moxa smoke) was applied to restrained mice 20 min per day, six days per week, for 12 weeks. At the end of the experimental period, we measured serum lipids and apolipoprotein, stained thoracic aortas and livers to observe pathological changes, and used immunohistochemical staining to assess the levels of α-smooth muscle actin, CD68, tumor necrosis factor-α, nuclear transcription factor-κB, and P38 mitogen-activated protein kinase. We also measured the levels of matrix metalloproteinase-2 and 9 and tissue metalloproteinase inhibitor-1. Results: After 12 weeks, lipid metabolism disorder and atherosclerotic plaques were observed in the ApoE−/- mice. Moxibustion or moxa smoke reduced the levels of serum total cholesterol, triglycerides, low density lipoprotein, and very low density lipoprotein but did not affect the levels of high density lipoprotein, apolipoprotein A1, or oxidized low density lipoprotein. Moxibustion or moxa smoke suppressed pathological changes in thoracic aortas and livers, increased fiber cap thickness, the fiber cap thickness/intimal medial thickness ratio, and collagen area percentage, and reduced extracellular lipids. Treatment with moxibustion or moxa smoke increased α-smooth muscle actin and reduced CD68 and the vulnerability index, suppressed tumor necrosis factor-α and nuclear transcription factor-κB expression, and did not affect P38 mitogen-activated protein kinase expression. Treatment lowered the levels of matrix metalloproteinase-2 and 9 and increased those of tissue metalloproteinase inhibitor-1. Conclusion: Moxibustion or moxa smoke exert protective effects in serum lipid profiles and carotid plaque stability in atherosclerotic mice by regulating plaque stability, inflammatory factors, and matrix metalloproteinases.