Atherosclerosis (AS) is one of the leading causes of cardiovascular disease and has a high rate of morbidity and mortality. Traditional Chinese Medicine (TCM) supplied many therapies for AS treatment for centuries. Among these treatments, BuYangHuanWu decoction (BYHWD) is a classic prescription. In this study, we analyzed the mechanisms of BYHWD in the treatment of AS by using a network pharmacology method. Our results revealed the mechanisms of BYHWD in treating AS, which is highly related to inflammation and apoptosis pathways, moreover, the genes including IL1β, TGFB1, TNF, IL6, NFκB1 are proved to be the key pharmacological targets for the treatment of AS. Furthermore, an AS rat model was established and the rats in the treatment group received different amounts of BYHWD. Serum lipid levels (TC/TG/HDL-C/LDL-C) and tissue oxidative stress levels (SOD, GSH-Px, CAT and MDA) were ameliorated in a dose-dependent manner. The morphology of the aortic intima in the BYHWD-treated groups was improved. Real-time PCR and Western blot analysis results indicated that inflammatory cytokines were suppressed and that the NF-κB signaling pathway was blocked by BYHWD. All of this evidence suggested that BYHWD is an ideal prescription for treating AS.