The study of a Hawaiian volcanic soil-associated fungal strain Penicillium herquei FT729 led to the isolation of one unprecedented benzoquinone-chromanone, herqueilenone A (1) and two phenalenone derivatives (2 and 3). Their structures were determined through extensive analysis of NMR spectroscopic data and gauge-including atomic orbital (GIAO) NMR chemical shifts and ECD calculations. Herqueilenone A (1) contains a chroman-4-one core flanked by a tetrahydrofuran and a benzoquinone with an acetophenone moiety. Plausible pathways for the biosynthesis of 1–3 are proposed. Compounds 2 and 3 inhibited IDO1 activity with IC₅₀ values of 14.38 and 13.69 μM, respectively. Compounds 2 and 3 also demonstrated a protective effect against acetaldehyde-induced damage in PC-12 cells.