Premature ovarian failure (POF) is a leading cause of female infertility, and there are no effective treatments. Although the pathogenesis is unclear, it appears to involve dysregulated signaling between BDNF and its receptor TrkB. However, BDNF can’t be used as a drug, so TrkB has never been considered as a therapeutic target for POF—until now. In a new study, researchers tested the effects of a TrkB agonist antibody, Ab4B19, in mice with POF induced by natural aging or cyclophosphamide. In both POF models, Ab4B19 increased the numbers of preantral and antral follicles and normalized gonadal hormone levels, ultimately improving fertility. Ab4B19 also attenuated gonadotoxicity and apoptosis in cyclophosphamide-treated mice. Further studies revealed that BDNF and TrkB expression were highly increased in human ovarian follicles during folliculogenesis, confirming the important role of BDNF-TrkB signaling in normal fertility. In contrast, in follicles of aged women, BDNF expression was downregulated. Notably, Ab4B19 activated TrkB signaling in human ovary samples ex vivo, validating its agonistic effects in human tissue. Although toxicological and clinical studies are needed, these preclinical findings identify TrkB as a potential therapeutic target for POF, providing hope for women who struggle with infertility.