<p>Alzheimer’s disease (AD) is associated with renin angiotensin system (RAS) overactivation that stimulates amyloid β-induced neurodegeneration. Activation of angiotensin II type 1 (AT₁) receptor impairs the protective phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway. The combination between angiotensin converting enzyme 2 (ACE2)/ angiotensin 1–7 (Ang 1–7) /Mas receptor (MAS1) axis activation and PI3K/Akt stimulation counteracts AT₁-induced apoptosis. Dapagliflozin (DAPA) alters the imbalance between the two RAS arms favoring the protective arm. Accordingly, the aim of the current study was to evaluate the possible neuroprotective effects of DAPA in guarding against scopolamine (SCO)-induced AD in rats <i>via</i> inhibiting RAS classical arm, and activating RAS protective arm, as well as PI3K/Akt pathway. DAPA administration suppressed ACE expression and reduced the levels of Ang II and AT₁ in the hippocampi, while elevated the hippocampal levels of ACE2 and Ang 1–7 in addition to boosting MAS1 hippocampal expression. Of note, DAPA prominently augmented the level of PI3K. Also it enhanced the activity of protein kinase A. Furthermore, the hippocampal levels of caspase-3, cytochrome-c, interleukin-6 and nuclear factor kappa B were suppressed, while guanine nucleotide-binding protein alpha-3 level was elevated by DAPA administration. DAPA also attenuated the histopathological SCO-induced damage in rats and enhanced their recognition memory and learning in novel object recognition test and Y-maze spontaneous alternation test. Hence, the current results represent the first evidence for proving that DAPA-induced activation of the protective RAS arm suppressed the cognitive deficits in SCO-induced AD in rats.</p>