BACKGROUND: Premature ovarian failure (POF) is defined as amenorrhea that occurs before the age of 40 when the ovaries weaken or even fail. This disease seriously affects a woman's future health and fertility. METHODS: Potential targets of Yijing Decoction (YJD) and POF were predicted by web-based pharmacology-related databases. The POF rat models and human ovarian granulosa cells injury models were induced by triptolide. In addition, the estrous cycle of the rats was monitored by vaginal smear and the ovarian tissue morphology was stained by HE staining. Immunohistochemistry, qRT-PCR and Western blotting were used to evaluate the levels of reproductive and angiogenesis related factors. Moreover, serum levels of the sex hormones and the oxidative stress indicators were measured by ELISA. RESULTS: YJD treatment resulted in the improvement of triptolide-induced abnormal ovarian function by restoring normal estrous cycle, maintaining nearly normal ovarian size, reducing follicular atresia and increasing vascularization. Additionally, YJD treatment normalized the serum levels of P, E2, FSH, LH, AMH, MDA and SOD, while activating the VEGF/VEGFR-2/FAK pathway. However, the VEGF/VEGFR-2/FAK pathway inhibitors reversed these pharmacological effects that YJD exhibited in POF rats. Furthermore, YJD increased the pregnancy rate and the number of live births in POF rats. CONCLUSION: YJD reduced oxidative stress level, promoted angiogenesis and improved ovarian function in POF rats by activating VEGF/VEGFR-2/FAK pathway. Moreover, YJD improved the intrauterine microenvironment for implantation in POF rats, thereby improving fertility. CLINICAL TRIAL NUMBER: Not applicable.