The present study aimed to investigate the anti-inflammatory effect of marine sponges of the genus Neopetrosia which are abundant in the Colombian Caribbean. We obtained three fractions from a total methanolic extract of Neopetrosia rosariensis and proxima. In vivo activity was measured using λ-carrageenan-induced paw edema assay. The in vitro inhibitory effects were evaluated on myeloperoxidase activity (MPO) and nitric oxide (NO), prostaglandin E2 (PGE2), and tumor necrosis factor alpha (TNF- α) production. Total extracts of N. rosariensis and N. proxima (100 mg/Kg) significantly inhibited the paw edema of rats (71.74% and 60.06%, respectively). Dichloromethane and methanol fractions of Neopetrosia sponges reduced MPO activity. Only, dichloromethane fraction of N. rosariensis significantly inhibited NO (66%), PGE2 (30.5%) and TNF-α production (72%). Our results show anti-inflammatory activity in extracts and fractions from species of marine sponges belonging to Neopetrosia genus and open the way for complementary studies to purify and identify active molecules.