<i>Perovskia artemisioides</i> is a perennial and aromatic plant widely distributed in the Baluchestan region of Iran. Phytochemical analysis of a <i>n</i>-hexane extract of <i>P. artemisioides</i> roots, guided by an analytical approach based on LC-ESI/LTQOrbitrap/MS/MS, yielded six previously undescribed diterpenoid compounds (<b>2</b>, <b>9</b>-<b>11</b>, <b>16</b>, and <b>20</b>), and 19 known diterpenoids, for which the structures were elucidated by 1D and 2D NMR experiments. Some of the isolated compounds showed significant anti-inflammatory activity using J774A.1 macrophage cells stimulated with <i>Escherichia coli</i> lipopolysaccharide. In particular, compounds <b>6</b>, <b>8</b>, <b>17</b>, <b>18</b>, <b>20</b>, and <b>22</b> significantly inhibited the release of nitric oxide and the expression of related pro-inflammatory enzymes, such as inducible nitric oxide synthase and cycloxygenase-2. Moreover, two compounds that showed the highest activity in reducing nitric oxide release (<b>6</b> and <b>18</b>) were tested to evaluate their effects on nitrotyrosine formation and reactive oxygen species release. Both compounds inhibited ROS release and, in particular, compound <b>6</b> also inhibited nitrotyrosine formation at all tested concentrations, thus indicating a significant antioxidant potential.