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Four new polyketides, namely furantides A–B (<b>1</b>–<b>2</b>), talamin E (<b>3</b>) and arugosinacid A (<b>4</b>), and two known polyketides were obtained from the mangrove-derived fungus <i>Penicillium</i> sp. HDN15-312 using the One Strain Many Compounds (OSMAC) strategy. Their chemical structures, including configurations, were elucidated by detailed analysis of extensive NMR spectra, HRESIMS and ECD. The DPPH radicals scavenging activity of <b>3</b>, with an IC₅₀ value of 6.79 µM, was better than vitamin C.