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Continuing chemical investigation of the Red Sea sponge <i>Spongia</i> sp. led to the isolation of four new 3,4-<i>seco</i>-3,19-dinorspongian diterpenoid lactones, secodinorspongins A−D (<b>1</b>−<b>4</b>), along with a classical spongian diterpenoid lactone, sponginolide (<b>5</b>). The chemical structures, including the absolute configurations of these compounds, were elucidated using the extensive spectroscopic study composed of 1D and 2D NMR data analyses, and a comparison between calculated-electronic-circular-dichroism (ECD) and experimental-circular-dichroism (CD) spectra. A plausible biosynthetic pathway of <b>1</b>−<b>4</b> was also proposed. Furthermore, the cytotoxicity, antibacterial and anti-inflammatory activities of <b>1</b>−<b>5</b> were evaluated. Compound <b>1</b> was found to exhibit inhibitory activity against the growth of <i>Staphylococcus aureus</i> (<i>S. aureus</i>), and <b>4</b> and <b>5</b> exhibited suppression of superoxide-anion generation and elastase release in fMLF/CB-induced human neutrophils.