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Four new compounds, including two new polyketides, heterocornols M and N (<b>1</b>, <b>2</b>), and a pair of epimers, heterocornols O and P (<b>3</b>, <b>4</b>), were isolated from the fermentation broth of the marine sponge-derived fungus <i>Pestalotiopsis heterocornis</i> XWS03F09, together with three known compounds (<b>5</b>&#8722;<b>7</b>). The new chemical structures were established on the basis of a spectroscopic analysis, optical rotation, experimental and calculated electronic circular dichroism (ECD). All of the compounds (<b>1</b>&#8722;<b>7</b>) were evaluated for their cytotoxic activities, and heterocornols M-P (<b>1</b>&#8722;<b>4</b>) exhibited cytotoxicities against four human cancer cell lines with IC₅₀ values of 20.4&#8722;94.2 &#956;M.