The phytochemical assessment of Pogostemon esquirolii resulted in the isolation and identification of sixteen sesquiterpenoids, including eudesmane-type (1-6, 9, and 11), bisabolane-type (8 and 10), caryolane-type (13-14), guaiacane-type (15-16), and other types (7 and 12). Of them, compounds 1-10, namely pogostesquines A-J, are ten previously undescribed ones. Compound 7 possessed an unusual backbone with the isopropyl group substituted at C-8 instead of C-7. Their structures were confirmed by extensive spectroscopic analysis, single-crystal X-ray diffraction analysis, and ECD calculations. All the compounds were reported from this plant for the first time. Biological evaluation revealed that compound 4 exhibited the most anti-neuroinflammatory activity by inhibiting NO production in LPS-induced BV2 mouse microglial cells. Subsequently, network pharmacology analyses indicated that compound 4 primarily alleviated neuroinflammation-induced cognitive dysfunction through the TNF signaling pathway. Molecular docking studies, molecular dynamics simulations techniques, and western blotting analysis further clarified that compound 4 could downregulate the expression of TNF-α and IL-6, and inhibit the activity of inflammation-associated inducible enzymes iNOS and COX-2. Concurrently, it was further demonstrated that compound 4 could inhibit the activation of NF-κB and MAPK signaling pathways via the TNF pathway.