Four previously undescribed highly oxygenated diterpenoids (1–4), zeylleucapenoids A–D, characterized by halimane and labdane skeletons, were isolated from the aerial parts ofLeucas zeylanica. Their structures were elucidated primarily via NMR experiments. The absolute configuration of1was established using theoretical ECD calculations and X-ray crystallographic analysis, whereas those for2–4were assigned using theoretical ORD calculations. Zeylleucapenoids A–D were tested for anti-inflammatory activity against nitric oxide (NO) production in RAW264.7 macrophages, of which only4showed significant efficacy with an IC50value of 38.45 μM. Further, active compound4was also evaluated for the inhibition of the release of pro-inflammatory cytokines TNF-αand IL-6 and was found to have a dose-dependent inhibitory effect, while it showed nontoxic activity for zebrafish embryos. A subsequent Western blotting experiment revealed that4inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, molecular docking analysis indicated that the possible mechanism of action for4may be bind to targets via hydrogen and hydrophobic bond interactions.