Abstract: The rice fermentation products of the fungus Scedosporium aurantiacum GXIMD 02519 were isolated and purified by silica gel column chromatography and semi-preparative liquid chromatography, etc. Their structures were characterized by various spectroscopic methods, including HR-ESIMS and NMR, etc. The inhibitory activity of nuclear factor kappa-B (NF-κB) and osteoclast differentiation of these compounds were determined by approaches of NF-κB luciferase reporter gene and tartrate-resistant acidic phosphatase (TRAP) staining. A new azaphilone, isochromophilone M (1), along with nine known compounds, were isolated and identified from the fungus S. aurantiacum GXIMD 02519, which were identified as 6-((1E, 3E)-3, 5-dimethylhepta-1, 3-dien-1-yl)-2, 4-dihydroxy-3-methylbenzaldehyde (2), barbatinic acid (3), botryorhodine B (4), 2, 6-dihydroxy-3, 4-dimethylbenzoic acid methyl ester (5), 2, 4-dihydroxy-3, 6-dimethylbenzoic acid (6), atranol (7), 4-methoxyphenylacetic acid (8), 4-hydroxybenzaldehyde (9), and scopararane C (10). Compounds 3 and 10 showed inhibitions of lipopolysaccharide (LPS)-induced NF-κB activation in RAW264.7 cells. Moreover, compound 10 could further inhibit receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation in bone marrow macrophages without observed cytotoxicity. This is the first report of the diterpene compound (10) as a potential inhibitor of osteoclast differentiation.