Chemical investigations of two collections of the deep reef Caribbean sponge Plakortis angulospiculatus resulted in the isolation of a new compound (1) along with the known compound spiculoic acid B (2) belonging to the spiculoic acid class and four other new compounds (3−6) belonging to the zyggomphic acid class. Three new aromatic compounds (7−9) were isolated from the Caribbean sponge Plakortis halichondrioides. The structural determination of the compounds was based on extensive NMR and mass spectroscopic analysis. The isolated compounds 1−7 were tested for their anti-inflammatory activity using in vitro assays for inhibition of inducible nitric oxide synthase and nuclear factor kappa B (NFκB) activity, as well as inhibition of intracellular reactive oxygen species generation as a result of oxidative stress. The cytotoxicity of these compounds was also evaluated to determine the selectivity index of their bioactivity with respect to cytotoxicity. Compounds 1 and 4 were more potent than the positive control in inhibiting NFκB activity and had IC50 values of 0.47 and 2.28 μM, respectively.