Background <p>Decreased ovarian reserve (DOR) seriously affects female reproductive health. However, the mechanism of DOR remains unknown. This study aimed to explore the mechanism of BDNF/TrkB/CREB signaling in granulosa cell pyroptosis and sex hormone secretion in DOR.</p> Methods <p>Recombinant BDNF (rBDNF) and TrkB antagonist ANA-12 were used to investigate the effects of the BDNF-TrkB signaling pathway on chronic unpredictable stress (CUS)-induced DOR in vivo. The mechanism of the BDNF-TrkB signaling pathway in NE-induced pyroptosis and sex hormone secretion was further investigated in vitro by the combined application of the CREB antagonist KG-501.</p> Results <p>The CUS model reduced BDNF expression in brain tissue, peripheral blood, and ovarian tissues and inhibited p-TrkB/TrkB, p-PI3K/PI3K, and p-AKT/AKT expression. rBDNF enhanced the ovarian index and improved histological structure in CUS mice, restored the disordered estrus cycle, reduced the serum corticosterone level, and increased the pregnancy rate and embryo number. rBDNF inhibited serum FSH, LH, and NE levels and apoptosis in CUS mice while increasing AMH, E₂, P, and T levels, accompanied by downregulated NLRP3, ASC, GSDMD-N, Cleaved Caspase-1, IL-18, and IL-1β levels. However, the ANA-12 effect on the above factors was opposite to that of rBDNF. Mechanistically, the BDNF-TrkB signaling pathway inhibited NE-induced pyroptosis of granulosa cells and sex hormone secretion disorders by promoting CREB phosphorylation.</p> Conclusion <p>Our findings indicate that the BDNF-TrkB signaling pathway inhibits pyroptosis of granulosa cells and sex hormone secretion disorders by promoting CREB phosphorylation, thereby improving DOR. These results provide a new theoretical basis in DOR for targeting the BDNF-TrkB-CREB axis.</p>