Phloretin (PHL), a dihydrochalcone flavonoid usually present in the roots and leaves of apple tree. In vitro study on GT1-7 immortalized hypothalamic neurons exposed to amyloid beta (25–35), demonstrated that PHL significantly influenced membrane fluidity and potential. PHL also significantly decreased excitotoxicity by restoring the calcium homeostasis in the same. Thus, PHL proves to be a promising therapeutic moiety which should be further screened in the treatment of Alzheimer's disease. The objective of the present study was to evaluate the nootropic, neuroprotective and neurotrophic roles of PHL in the subacute scopolamine induced amnesia in mice. In this study, mice were pretreated with PHL 2.5 mg/kg, 5 mg/kg, 10 mg/kg and Donepezil (DON) 1 mg/kg intraperitoneally (i.p) for 14 days. The last 7 days of treatment regimen included daily injection of SCP 1.5 mg/kg to induce cognitive deficits. Mice were subjected to behavioral analysis. Biochemical estimation of the brain homogenates for acetylcholinesterase and oxidative stress biomarkers were conducted. Furthermore, immunohistochemical analysis for the brain derived neurotrophic factor (BDNF) was carried out particularly in the hippocampus. PHL was found to significantly improve the performance of mice in Morris water maze test (P < 0.001) and significantly decreased the acetylcholinesterase activity (P < 0.001) at all doses compared to SCP treated mice. Also, PHL significantly elevated the activity of antioxidant enzymes viz. superoxide dismutase, catalase, reduced glutathione levels (P < 0.001) and decreased malonaldehyde levels (P < 0.001) in comparison with the SCP group. Immunohistochemistry revealed that PHL treatment dose dependently improved BDNF levels in the hippocampus which were found to be significantly depleted (P < 0.001) in the SCP group. Additionally, PHL (10 mg/kg) significantly enhanced the spatial memory formation (P < 0.05) and neurotrophicity (P < 0.001) compared to DON (1 mg/kg). The aforementioned research findings suggested that PHL has nootropic, neuroprotective and neurotrophic activities in SCP induced memory impaired mice and hence, is a promising therapeutic moiety in the treatment of AD.