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The hypothalamus–pituitary–ovary axis is the most important system for regulating female reproductive endocrine function. Its dysfunction would lead to the abnormal secretion of gonadotropin-releasing hormone, follicle-stimulating hormone, or luteinizing hormone, and eventually result in the occurrence of reproductive disease, such as congenital hypogonadotropic hypogonadism, polycystic ovary syndrome, and premature ovarian failure. Recently, an anti-aging gene, Klotho, has gained broad attention in female reproductive diseases. Reports have shown that Klotho is closely correlated to the hypothalamus–pituitary–ovary axis and plays a key role in the development and progression of reproductive diseases. With this issue, we generally review the physiological and pathological role of Klotho in the hypothalamus–pituitary–ovary axis. We also review the underlying mechanisms of Klotho in promoting and preventing female reproductive diseases, which involve the dysfunction of the fibroblast growth factor–Klotho endocrine system, the abnormal signaling regulation of Wnt-β-catenin and insulin-like growth factor-1, the accumulation of oxidative stress, and the inhibition of autophagy, eventually affecting the genesis, development, ovulation, or atresia of follicles. The present review would provide new insights and potential therapeutic target strategies for clinical strategies. [ABSTRACT FROM AUTHOR]