In the chemical study on the seeds of Caesalpinia sappan, six new cassane diterpenoids, phanginins R‒U (1‒3, 14) and caesalsappanins M and N (4 and 5), together with eight known compounds (6‒13), were isolated through comprehensive chromatography techniques, including column chromatography over silica gel, Sephadex LH-20, MCI and ODS, as well as preparative HPLC. Their structures were elucidated on the basis of NMR and HRESIMS analyses. The absolute configurations of compounds 1 and 4 were determined by CD spectrum. All isolated compounds were tested for their anti-proliferative effect against ovarian cancer A2780 and HEY cells. Compound 1 displayed significant anti-proliferative activity against both cell lines with the IC50 values of 9.9 ± 1.6 and 12.2 ± 6.5 µM, respectively. Furthermore, compound 1 dose-dependently induced A2780 cells apoptosis as evidenced by Hoechst 33342 staining, Annexin V positive cells, the up-regulated cleaved- PARP and the enhanced Bax/Bcl-2 ratio. What’s more, compound 1 also promoted the expression of the tumor suppressor gene p53. These findings indicate that cassane diterpenoids might have potential as lead compounds for development of anti-ovarian cancer agents.