Objective To investigate the mechanism of Shexiangtongxin dropping pills in the treatment of atherosclerosis (AS). Methods In this study, an AS animal model was established using ApoE-/- mice fed a high-fat diet, and the mice were divided into the blank group, model group, positive drug group, and low/medium/high-dose Shexiang Tongxin Dropping Pills groups. The therapeutic effect of Shexiang Tongxin Dropping Pills on AS mice was verified by detecting the serum levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), as well as by observing oil red O staining of aortic tissues. The effect of Shexiang Tongxin Dropping Pills on oxidative stress in AS mice was evaluated by measuring the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and the level of malondialdehyde (MDA) in the aorta using biochemical kits. The effect on inflammation in AS mice was assessed by detecting the expression levels of interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in the aorta via ELISA kits. Additionally, the effects on ferroptosis and the NRF2/GPX4 pathway in AS mice were investigated by detecting the expression levels of related proteins using RT-qPCR and Western blot. Results Shexiang Tongxin Dropping Pills reduced the serum levels of TC, TG, and LDL-C, increased the serum level of HDL-C, alleviated aortic plaque deposition, enhanced the activities of SOD and GSH-Px in the aorta, decreased the MDA level, and lowered the levels of IL-6, IL-1β, and TNF-α in AS mice. Meanwhile, Shexiang Tongxin Dropping Pills regulated the expression of ferroptosis-related proteins (FTL, Transferrin, Steap3) and proteins associated with the NRF2/GPX4 pathway (NRF2, GPX4, HO-1, ACSL4). Conclusion Shexiang Tongxin Dropping Pills can improve atherosclerosis by regulating the NRF2/GPX4 pathway, inhibiting ferroptosis, and suppressing oxidative stress and inflammatory responses.