As a commonly used first-line targeted drug, imatinib (Ima) is widely used first-line treatment for cancer patients. Patient survival is significantly prolonged, but Ima can cause premature ovarian failure (POF) and affect fertility. However, the underlying mechanism is unknown, and no effective method can be employed to improve this process. To investigate the effect of quercetin (Que) on Ima-induced POF and the underlying mechanism. The therapeutic impact of Que on Ima-induced POF in mice was clarified via molecular biology experiments and in vivo experiments in animals. To verify the underlying mechanism, network pharmacology was employed to construct a signaling network of Que-Ima-POF-related genes, followed by molecular biology and docking analysis. Network pharmacology analysis identified 38 therapeutic targets of Que in Ima-induced POF. The KEGG pathways of these genes were enriched for the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling pathway. Molecular docking analysis revealed that the epidermal growth factor receptor (EGFR) is a shared target of Que, Ima, and POF and has strong binding affinity. Hematoxylin-eosin (HE) staining and ELISA confirmed that Que can partially restore the ovarian index and function of mice with Ima-induced POF. Western blot, TUNEL, and immunohistochemical staining confirmed that Que promoted the PI3K/Akt signaling pathway and reduced apoptosis in Ima-induced POF mice. Thus, Que could inhibit apoptosis in Ima-induced POF by activating the PI3K/Akt pathway.