AIM: To elucidate the pharmacodynamic and network pharmacological mechanisms of total flavonoids of Carthamus tinctorius L., to explore their key targets and related pathways, and to clarify their mechanism of action against hepatic fibrosis. METHODS: The total flavonoids of Carthamus tinctorius L. were determined by LC-MS/MS and analysed for their compositions; the active ingredients were screened by TCMSP database, SWISS ADME database and literature search; the targets related to total flavonoids of Carthamus tinctorius L. were screened by Swiss Target Prediction database; and the targets related to hepatic fibrosis were screened by GeneCards database; the anti-hepatic fibrosis targets of total flavonoids of Carthamus tinctorius L. were obtained by taking the intersection of Venny.2.1.0; the protein interactions were analysed by STRING database; the visualization analysis was carried out by Cytoscape software; the GO function and KEGG pathway analysis was carried out by Metascape platform; and molecular docking was verified by using AutoDock software for the core targets and active ingredients. The mechanism of anti-hepatic fibrosis of total flavonoids of Carthamus tinctorius L. was verified by animal model and in vitro cell experiments. RESULTS: A total of 41 flavonoid components were identified in Carthamus tinctorius L. Through the network pharmacological analysis, 149 anti-hepatic fibrosis targets of total flavonoids of Carthamus tinctorius L. were obtained, including 23 core targets.The GO enrichment analyses involved a total of three aspects, namely, biological process (BP), cellular component (CC), and molecular function (MF). KEGG enrichment results showed that PI3K/Akt and MAPK are pathways involved in the development of hepatic fibrosis. Molecular docking verified that the active ingredients Quercetin, Acacetin and Glabridin were tightly bound to Akt1 and HIFIA, respectively. In animal model experiments, it was observed by HE and Masson staining that fibroplasia was reduced, collagen deposition was reduced, inflammatory cell infiltration was reduced, and fibrotic liver tissues were improved in total flavonoids of Carthamus tinctorius L. administration group. In isolated cell experiments: Western blotting results suggested that total flavonoids of Carthamus tinctorius L. could decrease the hepatic fibrosis marker factor α-SMA, Collagen1 (P<0.01) and PI3K, Akt protein expression (P<0.01). CONCLUSION: Total flavonoids of Carthamus tinctorius L. exerted anti-hepatic fibrosis effects through multi-components, multi-targets and multi-pathways, and their mechanism of action may be achieved by regulating the PI3K/Akt signalling pathway.