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Three new 5,5,6,6,5-pentacyclic spongian diterpenes, spongenolactones A–C (<b>1</b>–<b>3</b>), were isolated from a Red Sea sponge <i>Spongia</i> sp. The structures of the new metabolites were elucidated by extensive spectroscopic analysis and the absolute configurations of <b>1–</b><b>3</b> were determined on the basis of comparison of the experimental circular dichroism (CD) and calculated electronic circular dichroism (ECD) spectra. Compounds <b>1</b>–<b>3</b> are the first 5,5,6,6,5-pentacyclic spongian diterpenes bearing an <i>β</i>-hydroxy group at C-1. These metabolites were assayed for their cytotoxic, antibacterial, and anti-inflammatory activities. All three compounds were found to exert inhibitory activity against superoxide anion generation in fMLF/CB-stimulated human neutrophils. Furthermore, <b>1</b> showed a higher activity against the growth of <i>Staphylococcus aureus</i> in comparison to <b>2</b>.