Aim To investigate the effect of Shunshi three decoction of Chinese herbal medicine in patients with carotid atherosclerotic (CAS) plaque. Methods 94 patients with CAS plaque were randomly divided into two groups with 47 cases in each group. The control group was treated with one party a day, and the observation group was treated with Shunshi three decoction of Chinese herbal medicine. The course of treatment was four months. The clinical efficacy was observed in two groups, as well as the traditional Chinese medicine (TCM) syndrome scores, blood lipids (total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDLC), low density lipoprotein cholesterol (LDLC)), CD40/CD40L inflammatory signaling pathway, total plaque scores, carotid intima-media thickness (IMT), plaque area, liver and kidney function (alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine (Cr)) before and after treatment, and the adverse reactions were compared between the two groups. Results The total effective rate of the observation group after four months of treatment and six months after drug withdrawal (74.47% and 78.72%) was higher than that of the control group (46.81% and 44.68%, P＜0.05). After four months of treatment, there were no significant differences in the levels of ALT, AST, BUN, and Cr in the two groups compared with before treatment and between the two groups (P＞0.05); and there was no significant difference in the incidence of adverse reactions between the observation group (14.89%) and the control group (10.64%) (P＞0.05). After six months of drug withdrawal, the TCM symptom score of the observation group was lower than that of the control group (P＜0.05); the levels of interleukin-1 (IL-1), IL-6, soluble CD40 ligand (sCD40L) were lower in the observation group than those in the control group, while the level of IL-10 was higher than that in the control group (P＜0.05). The IMT, total plaque scores, and plaque area were lower in the observation group than those in the control group after six months of drug withdrawal (P＜0.05). Conclusion Compared with the conventional method of taking one dose a day, the use of the traditional Chinese medicine homeopathic three-dose method of taking Taohong Siwu decoction, Erchen decoction, and Simiao Yong'an decoction in the morning, afternoon, and evening, respectively, has shown more significant effects in terms of immediate efficacy, stable plaque area after drug withdrawal, and IMT, without significantly increasing adverse drug reactions and hepatotoxicity.