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Chemical study on marine sponge‐derivated fungus Aspergillus nidulans resulted in the isolation of seven depsidones (1–7) and two macrocyclic peptides (8 and 9). Their chemical structures were elucidated by extensive analyses of HRESIMS and NMR spectral data, as well as comparison with the literature. Compound 1 was an undescribed depsidone. All compounds exhibited significant antimicrobial activity (MICs: 2–128 μg/mL) towards at least one of seven microbial strains, including Bacillus cereus, Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella enterica, and Candida albicans. Of these, chlorinated depsidones (1–3, and 5) displayed potential antimicrobial activity. Nidulin (2) possessed good activity against tested strains except for S. enterica with MIC values in range of 2–16 μg/mL. Interestingly, undescribed depsidone 1 was selectively bioactive on the Gram‐positive bacteria (MICs: 2–4 μg/mL) and yeast (MIC: 8 μg/mL) but inactivity on the Gram‐negative bacteria (MICs: >256 μg/mL). Macrocyclic peptides, 8 and 9, displayed modest activity against E. faecalis strain with MIC values of 32 and 128 μg/mL, respectively.