Triptolide (TP), a diterpenoid triepoxide purified from the Chinese traditional medicine Tripterygium wilfordii Hook F (TWHF), possesses potent anti-tumor activities against several malignancies, including ovarian cancer. However, its short half-life in circulation and severe reproductive toxicity prohibit the clinical use of TP. In this study, we engineered novel nanoparticles consisting of calcium phosphate conjugated TP-loaded liposomes (TP@Lips-Ca/P), constituted of mPEGDPPE2000, to improve the circulation time, stability and biodistribution of TP. The average particles size was 134.1 nm, and the drug loading efficiency and encapsulation efficiency were 1.31 ± 0.13% and 72.31 ± 3.11% respectively. TP@Lips-Ca/P exhibits greatly enhanced anti-tumor effects on SKOV-3 ovarian cancer cells compared to TP alone. We further demonstrated that apoptosis of SKOV-3 cells induced by TP@Lips-Ca/P resulted from excessive accumulation of reactive oxygen species (ROS). ROS activates the MAPK signal pathway, leading to induction of apoptosis and inhibition of tumor growth. In addition, we found that TP@Lips-Ca/P displays significantly reduced toxicity toward the female reproductive system compared to free TP. In conclusion, TP@Lips-Ca/P nanoparticles are a promising novel chemotherapy approach for ovarian cancer.