Objective: In this study, we aimed to explore the effects of quercetin and flavonoids extracted from Cuscuta chinensis Lam. on tripterygium glycoside (TG)-induced premature ovarian failure (POF). Materials and Methods: Rats in the POF model were administered with 17β-estradiol (E2), quercetin, or flavonoids that were extracted from C. chinensis. Serum levels of anti-Müllerian hormone (AMH), luteinizing hormone (LH), follicular-stimulating hormone (FSH), and E2 were determined via enzyme-linked immunosorbent assay. The mRNA and protein expressions of PI3K-AKT signaling pathway- and apoptosis-related genes in the ovarian tissues were determined by immunohistochemistry, real-time polymerase chain reaction and western blot analysis. Results: After the administration of E2, quercetin, and flavonoids, there was a decrease in the estrus cycle, which was accompanied by an increase in weight and ovarian indices. TG reduced the thickness of the layer of granulosa cells in the antral follicles, the ratio of primitive follicles, secondary follicles, and sinusoidal follicles, and the number of cells in the corpus luteum and increased the ratio of atresia follicles; however, E2, quercetin, and flavonoids reversed these effects. In the POF group, serum levels of E2 and AMH were decreased, whereas FSH and FSH/LH levels were increased. TG downregulated the expression of PI3K, p-AKT, Atg5, and cyclin D2 and upregulated the expression of caspase-3. However, the changes in the levels of hormones and proteins were reversed after the administration of E2, quercetin, and flavonoids. Conclusion: Quercetin and flavonoids extracted from C. chinensis Lam. inhibited TG-induced POF by modulating the PI3K/AKT signaling pathway.