Objective. The purpose of our research is to systematically explore the multiple mechanisms of Hemerocallis fulva Flowers (HF) on depressive disorder (DD). Methods. The components of HF were searched from the literature. The targets of components were obtained from PharmMapper. After that, Cytoscape software was used to build a component-target network. The targets of DD were collected from DisGeNET, PharmGKB, TTD, and OMIM. Protein-protein interactions (PPIs) among the DD targets were executed to screen the key targets. Afterward, the GO and KEGG pathway enrichment analysis were performed by the KOBAS database. A compound-target-KEGG pathway network was built to analyze the key compounds and targets. Finally, the potential active substances and targets were validated by molecular docking. Results. A total of 55 active compounds in HF, 646 compound-related targets, and 527 DD-related targets were identified from public databases. After treated with PPI, 219 key targets of DD were acquired. The gene enrichment analysis suggested that HF probably benefits DD patients by modulating pathways related to the nervous system, endocrine system, amino acid metabolism, and signal transduction. The network analysis showed the critical components and targets of HF on DD. Results of molecular docking increased the reliability of this study. Conclusions. It predicted and verified the pharmacological and molecular mechanism of HF against DD from a holistic perspective, which will also lay a foundation for further experimental research and rational clinical application of DD.