Varieties of cellular stressors are reported to disrupt brain circuits or neuronal pathways that distribute neurotransmitter signals, resulting in subsequent genetic abnormalities, behavioral impairments, and/or mood disorders. For example, unfolded proteins accumulation in the endoplasmic reticulum (ER) induces ER stress-mediated cell death. Astringenin (AST) flavonoid functions as a neuroprotective agent and rescues neurons from various insults. However, the molecular mechanisms underlying the neuroprotective effects of Astringenin are still unclear. Rats received a single intraperitoneal (i.p.) injection of reserpine (RES) (5 mg/kg) or exposed to a single dose of 10 Gy head ionizing radiation (RAD) followed by AST treatment and sustained for 7 days. The expression of α-synuclein increased following head irradiation or reserpine administration, and endoplasmic reticulum stress factors were increased in brain tissue. AST administration results in upregulation of expression of AMPK and SIRT1, resulting in the inactivation of NF-κB p-65, FOXO1, and caspase-3. In addition, reduction of α-synuclein by AST improved the mobility-deficient behavior in rats. AST has also attenuated the decrease of dopamine, serotonin and BDNF levels. Moreover, AST upregulation of NRF2/HO1 levels was accompanied by enhancements of GSH content and SOD activity, and decreased inflammatory cytokines (TNF-α, IL-1β and IL-6). Such findings suggest that AST could be considered a promising agent that alleviates neuroinflammation by inhibiting ERs-mediated apoptosis signaling, and might possess a parkinsonism therapeutic effect.