Four new norsesquiterpene peroxides, named talaperoxides A–D (1–4), as well as one known analogue, steperoxide B (5, or merulin A), have been isolated from a mangrove endophytic fungus, Talaromyces flavus. Their structures were elucidated mainly by 1D and 2D NMR. Structures of 1,2, and 5were further confirmed by single-crystal X-ray diffraction, and their absolute configurations were also determined using copper radiation. Cytotoxic activities of compounds 1–5were evaluated in vitro against human cancer cell lines MCF-7, MDA-MB-435, HepG2, HeLa, and PC-3. Compounds 2and 4showed cytotoxicity against the five human cancer cell lines with IC50values between 0.70 and 2.78 μg/mL.