Introduction: The novel coronavirus disease 2019 (COVID-19) is in the midst of worldwide panic and global health concern since December 2019. In order to provide theoretical guidance for further clinical application in post-pandemic, we investigated active compounds and pharmacological mechanisms of ginseng to exert anti-depressant activity using network pharmacology, and discussed the active ingredients with immune-regulation and anti-depression. Materials and Methods: Information on compounds in ginseng was obtained from public databases, and genes related to depression were gathered using the Gene Cards database. Networks of ginseng-associated targets and depression-related genes were constructed through STRING database. Potential targets and pathway enrichment analysis related to the therapeutic efficacy of ginseng for depression were identified using Cytoscape and Database for Annotation, Visualization and Integrated Discovery (DAVID). Results: Network pharmacological analysis of ginseng in treatment of depression identified 16 active ingredients, 47 potential targets, 32 GO terms, and 8 target generegulated major pathways. Among them, kaempferol, beta-sitosterol, stigmasterol, fumarine and frutinone A are bioactive compounds and key chemicals. Core genes in PPI network were AKT1, CASP3, NOS3, TNF, and PPARG. Ginseng relieves depression by affecting biological processes associated with neurotransmitters, neurotrophic factors, neurogenesis, HPA axis and inflammatory response, which are reciprocally connected with each other. More importantly, we found that frutinone A and kaempferol are key ingredients in ginseng with dual activities of immune-regulation and anti-depression. Conclusion: Ginseng can regulate whole-body systems through a complex genes-interaction network, resulting in a certain effect on depression. This research demonstrates that ginseng is a preferable herb clinically in post-pandemic and network pharmacology approach can be an effective tool to reveal the mechanisms of traditional Chinese medicine from a holistic perspective.