Ligustilide (LIG) is a major active ingredient in traditional Chinese medicines that is also found in plant rhizomes such as carrot, coriander, and others, and it has been demonstrated to have cardiovascular preventive benefits. However, the mechanisms through which LIG protects the cardiovascular and cerebrovascular systems in atherosclerosis (AS) remain unknown. This study was aimed to investigate the mechanisms of LIG in AS utilizing the network pharmacology and molecular docking, and then to validate the putative mechanism through experiments. The network pharmacological analysis indicated that a total of 55 were performed on LIG and AS intersection targets. The genes of LIG and AS intersection targets enriched in the regulation of receptor and enzyme activity, cytokines-related, and transcription factors, indicating that these targets were primarily involved in cell proliferation and migration, regulating cell differentiation and skeletal activities in the development of AS. Finally, molecular docking was used to validate the major targets of LIG and AS intersection targets. Further experiments revealed that LIG may inhibit cell migration induced by AngII by reducing calcium influx, and regulating phenotypic translation-related proteins SM-22 alpha and OPN. The present study investigated the potential targets and signaling pathways of LIG, which provides new insight into its anti-atherosclerosis actions in terms of reducing inflammation, cell proliferation, and migration, and may constitute a novel target for the treatment of AS. Practical applications LIG has been shown to have cardiovascular protective benefits, the mechanism by which it protects the cardiovascular and cerebrovascular systems in AS remains unknown. This study uses a holistic network pharmacology strategy to investigate putative treatment pathways and conducts exploratory experimentation. The findings demonstrate that LIG reduces VSMC migration in the treatment of AS, acts as an anti-inflammatory agent, and prevents excessive cell proliferation and migration. Finally, the goal of our research is to uncover the molecular mechanism of LIG's influence on AS. The findings will provide a new research avenue for LIG as well as suggestions for the study of other herbal treatments. These research results will provide a new research direction for LIG and provide guidance for the research of other herbal medicines. This work revealed the multi-component, multi-target, multi-pathway, and multi-disease mechanism of LIG.