Ten new epipolythiodioxopiperazines (ETPs), namely, amphiepicoccins A-J (1-10), were isolated from the fish-gill-derived fungus Epicoccum nigrum HDN17-88. Their structures were deduced from extensive spectroscopic data and electronic circular dichroism (ECD) calculations. Amphiepicoccin A (1) which contains an aromatic indole motif is unprecedented among the epicoccin type of ETPs. Compounds 1, 3, and 6 displayed anti-HSV-2 activities, with IC50 values of 70, 64, and 29 μM, respectively (acyclovir as positive control with an IC50 value of 31 μM), while 5 and 6 also revealed inhibitory activity against Bacillus subtilis with minimum inhibitory concentration (MIC) values of 13 and 25 μM, respectively.