Eight previously unreported cembranoids (1–8), along with four known ones (9–12), have been isolated and identified from the soft coral Lobophytum crissum collected from the South China Sea under the guidance of HSQC-based DeepSAT analysis for targeted isolation. The structures of the new compounds were determined by comprehensive spectroscopic analysis, QM-NMR, TDDFT-ECD calculations, and comparison with reported literature data from analogs. In in vitro bioassays, all the isolated compounds have been screened for their antibacterial and antiproliferative activities.