Objective To investigate the effect of Xueguan Ruanhua Pill on microRNA-155 (miR-155), the suppressor of cytokine signaling-1(SOCS1)-phosphorylated signal transducer and activator of transcription 3 (p-STAT3)-programmed cell death factor 4(PDCD4) signaling pathway, and downstream inflammatory factors. Methods In the in vivo experiment, ApoE-/- mice were divided into model group, miR-155 inhibitor group, miR-155 mimic group, and high- and low-dose Xueguan Ruanhua Pill groups; pathological changes of the aorta were observed after 8 weeks of intervention, RT-PCR was used to measure the mRNA expression levels of miR-155,SOCS1,p-STAT3, and PDCD4 in the aorta, and ELISA was used to measure the serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interferon-γ (IFN-γ). In the in vitro experiment, RAW264.7 cells were randomly divided into control group (blank serum), miR-155 inhibitor group, miR-155 mimic group, and Xueguan Ruanhua Pill drug-containing serum group, and after intervention, RT-PCR was used to measure the mRNA expression levels of miR-155, SOCS1, p-STAT3, and PDCD4. Results The in vivo experiment showed that compared with the model group, the miR-155 mimic group and the high- and low-dose Xueguan Ruanhua Pill groups had a significantly lower degree of atherosclerosis in the aorta, as well as significant increases in the mRNA expression levels of miR-155 and SOCS1 in the aorta (P<0.05), significant reductions in the mRNA expression of p-STAT3 and PDCD4 in the aorta (P<0.05), and significant reductions in the serum levels of TNF-α, IL-6, and IFN-γ (P<0.05). The cell experiment showed that compared with the control group, the miR-155 mimic group and the Xueguan Ruanhua Pill drug-containing serum group had significantly higher mRNA expression levels of miR-155 and SOCS1 and significantly lower mRNA expression levels of p-STAT3 and PDCD4 in RAW264.7 cells (P<0.05). Conclusion Xueguan Ruanhua Pill exerts an anti-atherosclerotic effect by regulating the SOCS1/STAT3/PDCD4 signaling pathway through miR-155.