Triple-negative breast cancer (TNBC) is a lethal malignancy without safe and effective therapeutic drugs. In this study, the anti-TNBC bioassay-guided isolation of the medicinal plant <i>Croton kongensis</i> followed by the structural modification led to the construction of a small <i>ent</i>-kaurane diterpenoid library (<b>1</b>-<b>25</b>). With subsequent biological screening, 20 highly potent compounds (IC<sub>50</sub>s < 3 μM) were identified. Among them, 8,9-seco-<i>ent</i>-kaurane <b>6</b> displayed comparable activity (IC<sub>50</sub>s ∼ 80 nM) to doxorubicin but with better selectivity. The analysis of structure-activity relationships suggested that the cleavage of the C8-C9 bond and the presence of α,β-unsaturated ketone moiety were essential for the activity. The mechanistic study revealed that <b>6</b> induced apoptosis, autophagy, and metastasis suppression in TNBC cells via inhibition of Akt. <i>In vivo</i>, <b>6</b> significantly suppressed the TNBC tumor growth without causing side effects. All these results suggested that <b>6</b> may serve as a promising lead for the development of novel anti-TNBC agents in the future.