Total polysaccharides of lily bulb showed positive effects in reducing ovariectomized-induced anxiety, depression, and cognitive impairment, triggered the specific Ras/Akt/ERK/CREB signaling pathway, and modulated multiple proteins associated with mitochondrial oxidative stress. The potential mechanism was more closely associated with the predominant activation of estrogen receptors and regulation of brain regional neurotransmitters and neurotrophins with minor effects on the uterus. Here, BDNF is linked to depressive disorder.