Objective To predict and screen the active components and potential targets of Codonopsis Radix and Hedyotis Diffusae Herba in treatment of colorectal cancer by means of network pharmacology, and to investigate the mechanism of Codonopsis Radix and Hedyotis Diffusae Herba in the prevention and treatment for recurrence and metastasis of postoperative colorectal cancer.Methods The candidate components and potential targets of Codonopsis Radix and Hedyotis Diffusae Herba were screened out by traditional Chinese medicine systematic pharmacological (TCMSP) database, with oral bioavilability (OB) ≥30% and drug-like (DL) ≥18% as the parameters. The human genes corresponding to the medicine target sites were obtained from Uniprot database, and the genes corresponding to colorectal cancer from Genecard database. String tool was applied to build the disease-gene target protein-protein interaction (PPI) network, and then construct the component-target-disease network. Cytoscape software was used to merge the networks, and the core network for gene were screened out for GO function analysis and KEGG pathway enrichment analysis.Results A total of 28 active components were screened out from Codonopsis Radix and Hedyotis Diffusae Herba, and their corresponding targets were 469. A total of 196 human genes were obtained corresponding to the medicine target sites, as well as 8248 genes corresponding to colorectal cancer, 63 intersections of drug gene and disease gene, 63 nodes and 569 connections in the component-target-disease network. Gene GO function analysis suggested that the related mechanism involved molecular functions, cell components and biological process, and that colorectal cancer might be related to the regulation of proliferation of smooth muscle and epithelial cell, DNA binding transcription factor activity, blood circulation and response to nutrient levels, etc. Gene KEGG pathway enrichment analysis showed that the mechanism of colorectal cancer might be associated with P53 signaling pathway and PI3K/Akt signaling pathway.Conclusion The possible mechanism of Codonopsis Radix and Hedyotis Diffusae Herba in treating postoperative colorectal cancer may be related to the intervention of P53 signaling pathway and PI3K/Akt signaling pathway by their active components.This study provides a new direction for further study on the potential mechanism of Codonopsis Radix and Hedyotis Diffusae Herba in treating postoperative colorectal cancer.