Two novel compounds Yexiangniuside A (1) and B (2) along with six known sesquiterpene lactones 3-8 were isolated from the aerial parts of Vernonia cinerea. The structures of the isolated compounds were conclusively determined through extensive 1D and 2D NMR spectral analyses. The absolute configurations of 1 and 2 were proposed based on computational ECD spectrum predictions, and their molecular formulas were determined using high-resolution mass spectrometry (HR-ESI-MS). Subsequently, the anti-inflammatory activities of compounds 1-8 were evaluated in a lipopolysaccharide (LPS)-induced RAW 264.7 cells inflammatory model. The results demonstrated that compounds 1-5 significantly inhibited the activity of LPS-stimulated inflammatory factors (NO, TNF-α, IL-6, and IL-10) at concentrations ranging from 2.5 to 20 μM. These findings confirmed that compounds 1-5 are the basis for the anti-inflammatory activity of Vernonia cinerea.