Ten new epipolythiodioxopiperazines (ETPs), namely, amphiepicoccins A-J (<b>1</b>-<b>10</b>), were isolated from the fish-gill-derived fungus <i>Epicoccum nigrum</i> HDN17-88. Their structures were deduced from extensive spectroscopic data and electronic circular dichroism (ECD) calculations. Amphiepicoccin A (<b>1</b>) which contains an aromatic indole motif is unprecedented among the epicoccin type of ETPs. Compounds <b>1</b>, <b>3</b>, and <b>6</b> displayed anti-HSV-2 activities, with IC<sub>50</sub> values of 70, 64, and 29 μM, respectively (acyclovir as positive control with an IC<sub>50</sub> value of 31 μM), while <b>5</b> and <b>6</b> also revealed inhibitory activity against <i>Bacillus subtilis</i> with minimum inhibitory concentration (MIC) values of 13 and 25 μM, respectively.