Twelve sesquiterpene lactones were isolated from the whole plants of <i>Vernonia cinerea</i>. These included eight new compounds, vercinolides A-H (<b>1</b>-<b>8</b>), along with four known substances (<b>9</b>-<b>12</b>). The structures of the new compounds were determined by 1D and 2D NMR experiments and mass spectrometric methods. The absolute configurations of compounds <b>1</b>-<b>8</b> were determined by Mosher experiments and ECD data. Compounds <b>1</b>-<b>8</b> are the first examples of a new class of sesquiterpene lactones possessing a rare 4α,10α-ether ring and a 2,14-ether ring. Compounds <b>1</b>-<b>4</b>, <b>6</b>, <b>8</b>, <b>10</b>, and <b>12</b> were evaluated for their cytotoxic and anti-inflammatory activities. Compounds <b>10</b> and <b>12</b> exhibited inhibitory effects against nitric oxide production in lipopolysaccharide-activated RAW 264.7 mouse macrophage cells with IC<sub>50</sub> values of 21 and 23 μM, respectively. Both compounds were inactive for HeLa cells (IC<sub>50</sub> > 10 μM).