Chemical investigations on the acetone extract of the soft coral Lobophytum durum have afforded five new cembranoids with a trans-fused α-methylene-γ-lactone, durumolides A–E (1, 6, and 8–10), and five previously characterized cembrane-based diterpenoids (2–5 and 7). The structures of the isolated metabolites were elucidated through extensive spectroscopic analyses, while the relative stereochemistry of 4 was confirmed by X-ray diffraction analyses. Moreover, the absolute configurations of 3–5 and 8 were established by application of modified Mosher's method. The anti-inflammatory effects, antibacterial activities, and inhibition assay of HCMV (Human cytomegalovirus) endonuclease activity of these isolated metabolites 1–10 were evaluated in vitro.