ObjectiveThis study aimed to compare the mechanisms and efficacies of five formulas that improve blood circulation and remove blood stasis. Methods(1) A network pharmacology method was used to determine the targets of five formulas that promote circulation and remove blood stasis. Compounds of the five formulas, namely Danshen Yin (丹参饮, DSY), Huoluo Xiaoling Dan (活络效灵丹, HLXLD), Shixiao San (失笑散, SXS), Taohong Siwu Tang (桃红四物汤, THSWT), and Xuefu Zhuyu Tang (血府逐瘀汤, XFZYT), were retrieved from the Traditonal Chinese Medicine System Pharmacology Database (TCMSP), the Shanghai Institute of Organic Chemistry of CAS, and the TCM Integrated Database. Drug target network was constructed by searching the Swiss Target Prediction database and the STITCH database. The target network of stasis was extracted from the PharmGKB database, the Online Mendelian Inheritance in Man (OMIM) database, the Genetic Association Database (GAD), and the Therapeutic Target Database (TTD). Candidate targets were determined using protein–protein interaction (PPI) network extension and topology selection. Thereafter, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to determine the differentiation of the mechanism of the five formulas. (2) Animal experiments were conducted to explore the efficacies of the five formulas in treating blood stasis. Seventy New Zealand rabbits were exposed to high-fat feeding + epinephrine injection to construct a blood stasis syndrome model. The rabbits were evenly divided into control, model, DSY, HLXLD, SXS, THSWT, and XFZYT groups. The latter five groups were orally administered the corresponding formulas [DSY: 3.92 g/(kg·d), XFZYT: 7.10 g/(kg·d), SXS: 1.12 g/(kg·d), HLXLD: 5.60 g/(kg·d), THSWT: 4.48 g/(kg·d)]. Serum lipid and blood rheology were analyzed, and pathology slices were observed.Results(1) A total of 269, 358, 288, 370, and 376 candidate targets of DSY, HLXLD, SXS, THSWT, and XFZYT were obtained among which were 232 shared candidate targets. Fluid shear stress and atherosclerosis were the biological processes common to the five formulas. HLXLD, SXS, DSY, and THSWT regulated lipolysis in adipocytes, and XFZYT, HLXLD, SXS, and THSWT regulated the AGE-RAGE signaling pathway and complement and coagulation cascades. HLXLD, SXS, and XFZYT regulated the HIF-1 signaling pathway, DSY regulated the cGMP-PKG signaling pathway, HLXLD reduced platelet activation, SXS regulated the calcium signaling pathway, and XFZYT regulated the PPAR signaling pathway. (2) In the animal experiments, the values of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), TC/HDL, and TG/HDL in each group decreased, among which the ones seen in XFZYT, HLXLD, and SXS groups were statistically significant (P < 0.05). XFZYT presented the best effect, followed by HLXLD and SXS. XFZYT and HLXLD decreased apolipoprotein B100 (apoB100) and increased apolipoprotein A1/apoB100 (P < 0.05). XFZYT decreased all the values of hematocrit (HCT), plasma viscosity, whole blood viscosity (WBV); HLXLD and SXS affected HCT; and DSY and THSWT regulated WBV (P < 0.05). All the five formulas decreased the values of optical density and area of plaque, among which XFZYT and HLXLD showed statistical significance (P < 0.05). ConclusionAdjusting fluid shear stress and alleviating the injury of endothelial cells might be the common mechanisms by which the five formulas promote blood circulation and remove blood stasis. Different formulas also have unique targets, which may provide guidance for clinical drug selection. By regulating different indices, the five formulas can regulate blood lipid and hemorheology, improve the state of blood stasis, and decrease the degree of aortic plaque in the blood stasis model rabbits. XFZYT and HLXLD had higher efficacies than DSY, THSWT, and SXS.