Pre-clinical and clinical studies have suggested that sleep loss is a predisposing factor for neurodegeneration and memory impairments linked with Alzheimer’s disease (AD) and about 45% of AD patients show sleep disturbances. Sleep deprivation (SD) alters immuno-inflammatory, oxidantantioxidant enzymes balance and brain derived neurotrophic factor (BDNF) pathways which play significant role in the neurodegeneration and cognitive impairments associated with AD. Mangiferin (MGF), a C-glucosylxanthone, possesses multiple activities together with antioxidant, antiinflammatory, anti-anxiety, antidepressant and neuroprotection. The current study evaluated the beneficial effect of MGF (40 mg/kg, p.o.) and Piracetam (200 mg/kg, p.o.) pre-treatment (14 days) on chronic (5 days) SD-induced memory impairment, inflammation and BDNF depletion in both hippocampus (HC) and plasma as well as hippocampal oxidative damage in mice. MGF and Piracetam pre-treatment significantly improved the memory impairment by reducing escape latency while increasing number of crossings over platform position in Morris water maze (MWM) test. Recognition index also improved without affecting total exploratory time in novel object recognition (NOR) test by MGF and Piracetam pre-treatment. MGF and Piracetam pre-treatment attenuated SD-induced neurodegeneration by reducing inflammatory cytokines (IL-1β, TNF-α and IL-6) in both plasma and HC as well as hippocampal oxidative stress via decreasing lipid peroxidation along with restoration of glutathione level in HC. Chronic pre-treatment of MGF and Piracetam also prevented the SD evoked decrease in plasma and hippocampal BDNF level in mice. In conclusion, findings of the present study suggests that MGF showed significant beneficial effect against SD-induced neurodegeneration and memory impairments which may be attributed to its inhibitory action on pro-inflammatory cytokines, oxidative damage and depletion of BDNF level in both plasma and HC. These findings support the potential applicability of MGF in the management of neurodegeneration and memory impairments often seen in neurological disorders linked with inflammation, oxidative stress and BDNF pathway.