Ethnopharmacological relevanceSijunzi Decoction(SJZD), as a famous classical prescription for the treatment of colorectal cancer(CRC) in the traditional Chinese medicine (TCM), has achieved good curative effects in clinical practice. However, its specific ingredients and molecular mechanisms is still unclear. Aim of the studyTo analyze the effective ingredients and molecular mechanisms of SJZD in the treatment of CRC through network pharmacology technology and experimental validation. Materials and methodsFirst, the TCM Systems Pharmacology database and analysis platform database were searched to screen the effective chemical components of SJZD. Swiss Target Prediction was used to predict corresponding potential target genes of compounds. After that, we constructed a components and corresponding target network by Cytoscape. Simultaneously, 5 disease databases were used to search and filter CRC targets, and then we constructed a drug-disease target protein-protein interaction (PPI) network. Cytoscape 3.7 was used for visualization and cluster analysis, and Metascape database was used for GO and KEGG enrichment analysis. We drew the main pathway-target network diagram. Autodock vina1.5.6 was applied to molecular docking for the main compounds and target proteins. Subsequently, the potential mechanism of SJZD on colon cancer predicted by network pharmacological analysis was experimentally studied and verified in vivo and in vitro. Results144 effective active chemical components, 897 potential targets, and 2584 CRC target genes were screened out. The number of common targets between the SJZD and CRC was 414.3250 GO biological process items and 186 KEGG signal pathways were obtained after analysis. The main compounds and the target protein had a good binding ability in molecular docking. The results of cell and animal experiments showed that SJZD could promote apoptosis and autophagy of CRC cells through PI3K/Akt/mTOR pathway. ConclusionsSJZD can treat CRC through multiple components, multiple targets and multiple pathways. We initially revealed the effective components and molecular mechanisms of SJZD in the treatment of CRC, and we used molecular docking and experiment for preliminary verification.