Zinc deficiency has many adverse effects, including growth retardation, loss of appetite, vascular diseases, cognitive and memory impairment, and neurodegenerative diseases. In the current study, we investigated the hypothesis that dietary zinc inadequacy affects neurotrophic factors and proteostasis in the brain. Three weeks old Wistar/Kyoto male rats were fed on either a zinc-deficient diet (D; <1 mg zinc /kg diet; n=18) or pair-fed with the control diet (C; 48 mg Zn /kg diet; n=9) for a period of 4 weeks. Subsequently, the rats in the D group were subdivided into two groups (n=9), in which one group continued to receive a zinc deficient diet while the other received zinc supplemented diet (R; 48 mg Zn/kg diet) for three more weeks after which rats were sacrificed to collect brain tissue. Markers of ER stress, ubiquitin-proteasome system (UPS), autophagy, and apoptosis, along with neurotrophic factors, were investigated by immunoblotting, and the proteasomal activity was analyzed by the spectrofluorometric method. The results showed altered UPS and autophagy components and increased gliosis, ER stress, and apoptosis markers in zinc-deficient rats compared to the control group. Zinc repletion for three weeks could partially restore these alterations, indicating a necessity for an extended duration of zinc supplementation. In conclusion, a decline in zinc levels below a critical threshold may trigger multiple pathways leading to brain-cell apoptosis.