Dysideanones A-C (1-3), three unusual sesquiterpene quinones with unprecedented carbon skeletons, were isolated from the South China Sea sponge Dysidea avara. Their structures including absolute configurations were determined by a combination of spectroscopic analyses and calculated ECD spectra. Within the sesquiterpene quinone structures, dysideanones A (1) and B (2) share an unprecedented 6/6/6/6-fused tetracyclic carbon skeleton, while dysideanone C (3) possesses an unusual 6/6/5/6-fused tetracyclic core. Dysideanone B (2) showed cytotoxicity against two human cancer cell lines, HeLa and HepG2, with IC50 values of 7.1 and 9.4 μM, respectively.