Objective Objective Based on the network pharmacology approach, this paper aimed to study the useful material base and functioning mechanism of Gardenia jasminoides Ellis-processed Ligusticum for the treatment of depression. Their antidepressant effects were initially tested and verified using ICR( Institute of Cancer Research) mice. Methods Effective compounds of Gardenia jasminoides Ellis-processed Ligusticum wallichii were collected from the Web of Science, CNKI, and ScienceDirect Databases. Then, the chosen ingredients were further selected or screened according to their generic drug-like principle. The Swiss Target Prediction Database and GeneCards were used to predict and identify the target components with antidepressant activity. Furthermore, the String Database was used to annotate protein interactions, and ClueGO software was used to perform the enrichment analysis of concentrated signal passages for those key functioning targets of the antidepressant activity. Based on the above information, the “ ingredient-target-signal-pathway” network was constructed, and its topological analysis was conducted by Cytoscape 3. 7. 0 software. Based on the result of this analysis, the top 4 compounds were tested for their antidepressant effect in ICR mice. Results Based on Cytoscape 3. 7. 0 software, the active ingredients with antidepressant effects were 4-methoxyl-phenethyl-butyl ether, jasminoside J, Gardenal-I, and butylphthalide. The main effective targets were COMT, HTR1A, DRD 2, SLC6A4, SLC6A3, MAOA, GRM5, DRD4, DRD3, HTR2A, HTR3A, GRIA1, APP, HTR1B, and GRM1. The main pathways of antidepressants were serotonergic and dopaminergic synapses. Animal experiments showed that the positive control groups, the medium and high dose groups of butylphthalide and Gardenal-I, and the high dose groups of 4-methoxyl-phenethyl-butyl ether could significantly reduce the immobility time compared with the blank groups, which further verified the antidepressant activity of these ingredients. Jasminoside J could not reduce the immobility time, indicating that it did not show an antidepressant effect. Conclusions Based on network pharmacology and animal experiments, the active ingredients with antidepressant activity were 4- methoxyl-phenethyl-butyl etherGardenal-I, and butylphthalide, which provide references for further research.