Objective. We aimed to investigate the mechanisms underlying the effects of the Cyperi Rhizoma-Chuanxiong Rhizoma herb pair (CCHP) against depression using a network pharmacology approach. Methods. A network pharmacology approach, including screening of active compounds, target prediction, construction of a protein-protein interaction (PPI) network, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and molecular docking, molecular dynamics (MD) simulations, and molecular mechanics Poisson–Boltzmann surface area (MMPBSA), were used to explore the mechanisms of CCHP against depression. Results. Twenty-six active compounds and 315 and 207 targets of CCHP and depression, respectively, were identified. The PPI network suggested that AKT1, IL-6, TP53, DRD2, MAPK1, NR3C1, TNF, etc., were core targets. GO enrichment analyses showed that positive regulation of transcription from RNA polymerase II promoter, plasma membrane, and protein binding were of great significance. Neuroactive ligand-receptor interaction, PI3K-Akt signaling pathway, dopaminergic synapse, and mTOR signaling pathway were important pathways. Molecular docking results revealed good binding affinities for the core compounds and core targets. MD simulations and MMPBSA validated that quercetin can stably bind to 6hhi. Conclusions. The effects of CCHP against depression involve multiple components, targets, and pathways, and these findings will promote further research on and clinical application of CCHP.