Esophageal squamous cell carcinoma (ESCC) is one of the most frequently occurring diseases in the world. (RR) has been demonstrated to be effective against ESCC; however, the mechanism is unknown. The primary gene modules related to the clinical characteristics of ESCC were initially investigated in this research using weighted gene co-expression network analysis (WCGNA) and differential expression gene (DEG) analysis. We employed network pharmacology to study the hub genes linked with RR therapy on ESCC. A molecular docking simulation was achieved to identify the binding activity of central genes to RR compounds. Lastly, a chain of experimentations was used to verify the inhibitory effect of RR water extract on the ESCC cell line . The outcomes revealed that CCNA2, TOP2A, AURKA, CCNB2, CDK2, CHEK1, and other potential central targets were therapeutic targets for RR treatment of ESCC. In addition, these targets are over-represented in several cancer-related pathways, including the cell cycle signaling pathway and the p53 signaling pathway. The predicted targets displayed good bonding activity with the RR bioactive chemical according to a molecular docking simulation. experiments revealed that RR water extracts could inhibit ESCC cells, induce cell cycle arrest, inhibit cell proliferation, increase P53 expression, and decrease CCNA2, TOP2A, AURKA, CCNB2, CDK2, and CHEK1. In conclusion, our study reveals the molecular mechanism of RR therapy for ESCC, providing great potential for identifying effective compounds and biomarkers for ESCC therapy.