Three unusual meroterpenoids, septosones A–C (1–3), were isolated from the marine sponge Dysidea septosa. The structures were determined by analysis of spectroscopic data combined with single-crystal X-ray diffraction and ECD calculations. Septosone A (1) features an unprecedented “septosane” carbon skeleton, whereas septosones B (2) and C (3) share a rare spiro[4.5]decane motif. Septosone A showed in vivo anti-inflammatory activity in CuSO4-induced transgenic fluorescent zebrafish likely through inactivation of the NF-κB signaling pathway.