Our previous studies demonstrated that Qi-Shao-Shuang-Gan (QSSG), a combination of Astragalus membranaceus saponins (SAM) with Paeonia lactiflora glycosides (GPL), possessed protective effects against sepsis in mice. The present study aimed to explore its underlying mechanisms with a focus on the adhesion between leukocytes and inflammatory endothelial cells. Our results showed that QSSG (10, 30, 100 μg/ml) concentration-dependently inhibited the adhesion between leukocytes and lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs), and downregulated the expressions of endothelial adhesion molecules such as E-selectin, P-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in HUVECs. It also suppresssed the phosphorylations of JNK, ERK and p38 MAPK, as well as the activation of NF-κB in HUVECs. The findings revealed that QSSG was able to prevent the adhesion between leukocytes and endothelial cells, which supported a plausible explanation for the antiseptic effects of QSSG.