Nine new sesquiterpenoid lactones and 11 known analogues were isolated from the aerial parts of Salvia plebeia R.Br. Their structures were elucidated via HRESIMS and NMR data, and their absolute configurations were defined via electronic circular dichroism data, X-ray crystallographic analysis, and the modified Mosher's ester method. Compounds 1-20 were investigated for their ability to inhibit LPS-stimulated nitric oxide production in murine macrophage cells. Of the isolates, epi-eudebeiolide C (20) showed the highest inhibitory effect (IC50 of 17.9 μM). mRNA and protein expression of inducible nitric oxide synthase (iNOS), but not that of cyclooxygenase-2 (COX-2), was dose-dependently decreased by 20 in LPS-activated RAW 264.7 cells. Based on a mechanistic study involving the nuclear factor-κB (NF-κB) signaling pathway, the anti-inflammatory effect of 20 was attributed to NF-κB activation blockade via inhibition of NF-κB (IκB) phosphorylation. Therefore, 20 might be a potential candidate for relieving inflammatory diseases.