Eleven new ophiobolin-type sesterterpenoids, asperophiobolins A-K (<b>1</b>-<b>11</b>), along with 12 known analogues (<b>12</b>-<b>23</b>) were isolated from the cultures of the mangrove endophytic fungus <i>Aspergillus</i> sp. ZJ-68. The structures of the new compounds were elucidated through spectroscopic analyses, and their absolute configurations were assigned by a combination of Mo<sub>2</sub>(AcO)<sub>4</sub>-induced electronic circular dichroism spectra and quantum chemical calculations. Asperophiobolins A-D (<b>1</b>-<b>4</b>) represent the first examples possessing a five-membered lactam unit between C-5 and C-21 in ophiobolin derivatives. In the bioactivity assays, compounds <b>8</b>-<b>10</b> and <b>14</b>-<b>17</b> exhibited inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophage cells with IC<sub>50</sub> values ranging from 9.6 to 25 μM, and compound <b>8</b> was found to show comparable inhibition of <i>Mycobacterium tuberculosis</i> protein tyrosine phosphatase B with an IC<sub>50</sub> value of 19 μM.