The Tiaopi Huxin recipe (TPHXR) is widely used in traditional Chinese medicine for the clinical treatment of coronary heart disease. However, the mechanism of TPHXR treatment of atherosclerosis (AS) has not been fully elucidated. In this study, we have aimed to explore the potential antiatherosclerotic effect of TPHXR and its underlying mechanisms. Male ApoE knockout (ApoE-/- ) mice were fed a high-fat diet for 12 weeks and were randomly divided into four groups: the control group, and the low-dose, medium-dose, and high-dose TPHXR groups. The nitric oxide (NO) levels in arterial tissue and human umbilical vein endothelial cells (HUVECs) were measured by diaminofluorescein-2 diacetate staining. Vasorelaxation of mice aorta was performed by wire myograph. Inflammatory cytokines, including tumor necrosis factor-α (TNF-α), hs-CRP, IL-6, and IL-1β, in mice plasma were analyzed by enzyme-linked immunosorbent assay. Western blot analysis was applied to observe protein expression. Oil Red O staining was utilized for the quantification of atherosclerotic plaques. Results showed that 4 weeks of high- and medium-dose TPHXR treatment by oral gavage reduced atheromatous lesions in ApoE -/- mice. The high- and medium-dose TPHXR treatment, but not the low-dose treatment, promoted eNOS phosphorylation, increased NO levels and improved endothelium-dependent vasorelaxation in ApoE -/- mice. High- and medium-dose TPHXR, but not low-dose TPHXR, decreased the expression of cav-1, NF-κB p50, NF-κB p65, ICAM1, VCAM-1, TNF-α, IL-6, and IL-1β in the vasculature of ApoE -/- mice. Enzyme-linked immunosorbent assay analysis indicated that high- and medium-dose TPHXR decreased the levels of TNF-α, IL-6, hs-CRP, and IL-1β. In conclusion, our findings show that TPHXR improved the endothelial function and reduced atheromatous lesions in ApoE -/- mice. This result may be due to the decreased expression of caveolin-1 and NF-κB and, hence, the attenuated inflammatory response in AS mice vasculature. TPHXR may represent a promising intervention in patients with AS. © 2019 Wiley Periodicals, Inc.