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Background: Na+‐Ca2+ exchanger isoform‐3 (NCX3) take‐parts in the aberrant Ca2+‐influx seen during neuronal excitotoxicity. However, the NCX3‐Aβ1‐42‐associated cytotoxicity and whether renovation of the aggregated Aβ1‐42‐induced NCX3 downregulation prevents or delays the onset of Alzheimer's disease (AD) and AD‐related pathology remain unclear. Withania somnifera (W. somnifera), an indigenous traditional medicinal plant, has a long history of uses in preventing aging‐related neurological‐health impairments. However, this plant's roots extract therapeutic value in neurodegenerative diseases, such as AD, albeit far less well studied. Methods: Microscopic fluorescence and haemocytometer cell viability counting were performed to examine contributions of NCX3 against Aβ1‐42‐induced cytotoxicity in BHK‐cells. Authenticated W. somnifera‐dried‐roots were powdered, and the powder's methanolic extract was used for phytochemical screening of the roots‐bioactive constituents and the 5×FAD mice gavage treatments from postnatal day 30 (P30) to P60 while maintaining their daily bodyweight records. After treatments, in vivo‐cognitional studies and then neurochemical‐examinations of the NCX3 immunoblot expression level, a sandwich ELISA and microscopy of Aβ plaque deposition, and antioxidant activity assays were performed in the AD‐associated brain regions at the mice age of 4 months. Results: The cell‐based studies revealed positive roles of NCX3 in the resistance against Aβ1‐42 exposure toxicological damages. Phytochemical screening of the extract attested presence of antioxidants as major bioactive constituents of the roots. The mice recorded bodyweights during treatments statistical‐analysis evidenced that the extract has no potential toxicity. The cognitional studies data indicates that the treatment group mice showed significant improvements than vehicles (p<0.01). Interestingly, subsequent studies in the mice's cortex‐ and hippocampus‐homogenates showed that the W. somnifera prevents NCX3 suppression, significantly reduces Aβ1‐42 expression, and normalizes oxidative stress. Moreover, confocal microscope immunoreactive studies indicated reduced depositions and distributions of Aβ plaques in the treatment group AD‐associated brain tissues. Conclusion: These findings suggest the relevance of NCX3 against effects of Aβ1‐42‐associated cytotoxicity and that the W. somnifera antioxidant constituent's bioactivity with no indications of toxicity, operating against Aβ‐induced NCX3 downregulation, may have a therapeutic role for augmenting NCX3 physiological properties in the maintenance of ionic Ca2+ homeostasis and ameliorates cognition in the 5×FAD mouse‐model, and therefore, might be valuable in AD‐pharmacological medicine. [ABSTRACT FROM AUTHOR]