Background: Curcumae Radix (CR), derived from the dry roots of Curcuma longa L., family Zingiberaceae, is widely used to treat depression. However, the ingredients and mechanisms of CR are still unclear. The purpose of this study was to solve this problem using network pharmacology and molecular docking. Methods: The active ingredients of CR were screened through TCMSP, and the depression-related genes were obtained through the Genetic Association, GeneCards, and OMIM databases. Then, DisGeNET score was performed to evaluate the correlation between co-genes and depression. Topological analysis was conducted to screen hub genes and proteins, molecular docking was performed to evaluate the binding ability of the hub protein with active ingredients, and gene ontology (Go) function analysis, gene tissue localization, and KEGG pathway analysis were conducted to explore the function and location of genes, as well as the mechanism of CR for treating depression. Results: Eight ingredients of CR were screened based on pharmacokinetic properties, five of which are closely related to depression, including (E)-5-hydroxy-7-(4-hydroxyphenyl)-1-phenyl-1-heptene, (E)-1,7-diphenyl-3-hydroxy-1-hepten-5-one, oxycurcumenol, beta-sitosterol, and sitosterol. They interacted with 45 co-genes and co-proteins with a DisGeNET score >= 0.3. AR, NOS2, PTGS2, and TYK2 were pivot genes. EGFR, PTGS2, HSP90AA1, MAPK8, and ESR1 were hub proteins. PTGS2 was found to have good binding potential with oxycurcumenol, (E)-1,7-diphenyl-3-hydroxy-1-hepten-5-one and (E)-5-hydroxy-7-(4-hydroxyphenyl)-1-phenyl-1-heptene. Go functional analysis indicated that co-genes involved complex biological processes, cellular components and molecular functions. PER2, P2RX7, GRM1, TACR1, MAPK8, HCRTR1, EGFR, and TYK2 were highly expressed in the prefrontal cortex. The potential pathways for CR to exert antidepressant effects were calcium, estrogen, PI3K-Akt and ErbB signaling pathways. Conclusions: This study revealed the ingredients, effective targets and mechanisms of CR in the treatment of depression, which provides a new perspective for the development of new antidepressants.