The neuro-endocrine-immune (NEI) system plays a critical regulatory role in modulating host homeostasis and optimizing health. We created the dbNEI 2 years ago to collect NEI molecules and interactions. For transferring the conceptual NEI to the systematic NEI network and uncovering the NEIs medical function, we updated the dbNEI 2.0 in three ways: (i) extended NEI molecules to 2242 genes and 7657 chemical compounds by using gene ontology-based (GO-based) data mining strategy, (ii) added multilayer interactions of NEI molecules including KEGG signal transduction and metabolic pathways, HPRD protein-protein interactions (PPI), transcription factor and microRNA regulations and (iii) connected 611 drugs and 823 diseases through multilayer NEI interactions. The reconstructed drug-NEI-disease network will facilitate the systematic study of NEI system.