The new modified eremophilanes hastatusins A-K (<b>1</b>-<b>11</b>) and 13 known compounds (<b>12</b>-<b>24</b>) were isolated from <i>Parasenecio hastatus</i>. The structures of <b>1</b>-<b>24</b> were elucidated based on spectroscopic data analysis and comparison with literature data. The absolute configurations of compounds <b>1</b> and <b>2</b> were defined by single-crystal X-ray diffraction analysis, and the other new compounds were assigned based on ECD data. This work is the first report of the crystal structure of an 8,9-<i>seco</i>-eremophilanolide (<b>1</b>) with two lactone units. The enantiomers of <b>1</b> were separated by chiral-phase HPLC, and the absolute configurations of (-)-<b>1</b> and (+)-<b>1</b> were established via experimental and calculated ECD data. The new compounds represent four unusual skeletons: a modified 8,9-<i>seco</i>-eremophilane featuring a rare 6,9;8,12-dilactone moiety (<b>1</b>), a furanoeremophilane-type skeleton (<b>2</b>-<b>7</b>, <b>11</b>), a rare C<sub>14</sub> <i>nor</i>-eremophilane-type skeleton (<b>8</b>, <b>9</b>), and a modified eremophilane lactone-type skeleton (<b>10</b>). All isolates were assayed for their neuroprotective effects against H<sub>2</sub>O<sub>2</sub>-induced SH-SY5Y cell injury, and compounds <b>2</b>-<b>5</b>, <b>12</b>, <b>21</b>, and <b>23</b> exhibited activities even at a low concentration of 1 μM. Compounds <b>6</b>-<b>9</b>, <b>13</b>, <b>14</b>, <b>17</b>, <b>20</b>, <b>22</b>, and <b>24</b> also showed notable effects at 10 and 100 μM.