Fifteen new diterpenoids, namely xishaklyanes A-O (1–15), along with three known related ones (16–18), were isolated from the soft coralKlyxum mollecollected from Xisha Islands, South China Sea. The stereochemistry of the new compounds was elucidated by a combination of detailed spectroscopic analyses, chemical derivatization, quantum chemical calculations, and comparison with the reported data. The absolute configuration of compound18was established by the modified Mosher’s method for the first time. In bioassay, some of these compounds exhibited considerable antibacterial activities on fish pathogenic bacteria, and compound4showed the most effective activity with MIC of 0.225 μg/mL againstLactococcus garvieae.