Five new secondary metabolites, modiolides D-G (1-4) and 1-(2,5-dihydroxyphenyl)-3-methoxy-butan-1-one (8), one new natural product, 1-(2,5-dihydroxyphenyl)-3-hydroxybutan-1-one (7), along with three known compounds, modiolides A (5) and B (6), and 1-(2,5-dihydroxyphenyl)-2-buten-1-one (9) were isolated from a fermentation culture of the marine endophytic fungus Paraconiothyrium sp. VK-13. Their chemical structures were elucidated by the NMR and MS spectroscopic analysis as well as the modified Mosher's method. Compounds 7 and 9 inhibited the overproduction of proinflammatory mediators NO and PGE2 in LPS-stimulated RAW264.7 cells, with IC50 values ranging from 3.9 to 12.5 µM. The inhibitory effects of 7 and 9 on the release of NO and PGE2 were correlated with their significant suppression of iNOS and COX-2 protein expression, respectively. Furthermore, both compounds 7 and 9 inhibited the mRNA expression of proinflammatory cytokines, including TNF-α, IL-1β, IL-6, and IL-12, with IC50 values in a range of 2.4-12.5 µM.