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A new 12-membered resorcylic acid lactone, cochliomycin H ( 1 ), and one known resorcylic acid lactone, O -demethylated-zeaenol ( 2 ), were isolated from sponge-derived fungus Curvularia sp. ZYX-Z-4. The structure of 1 was elucidated by 1D and 2D NMR spectroscopic as well as HR-ESI-MS analysis. The configuration of 1 was established by the NMR chemical shifts calculation followed by DP4+ analysis and ECD calculation. Compounds 1 and 2 were evaluated for the antifungal and neuroprotective activities and compound 2 showed comparable neuroprotective effect on the H 2 O 2 injured SH-SY5Y cells to that of trolox.