Hibiscus sabdariffa L. (Malvaceae) is one of the well-known traditionally used remedy worldwide. It exhibited numerous pharmacological properties including antioxidant, antidepressant, sedative, anti-inflammatory, antiproliferative, antimicrobial and neuroprotective activities. The aim of this study is to highlight the mechanisms underlying the neuroprotective effects of anthocyanin-enriched extracts of two Hibiscus varieties (white and red calyces) in the management of Alzheimer’s disease (AD) in addition to their metabolic profiling. The anthocyanin contents were determined quantitatively using the pH-differential technique and qualitatively by LC/MS/MS. The extracts were tested in vitro for their antioxidant potential as well as acetylcholinesterase inhibition activity and both showed promising activities. The LC/MS/MS analysis allowed the tentative identification of 26 and 24 metabolites in red and white calyces, respectively, represented by anthocyanins, flavonoids, aliphatic and phenolic acids. In vivo, streptozotocin induced AD in mice model was established and Hibiscus extracts were tested at a dose of 200 mg kg⁻¹ compared to celecoxib (30 mg/kg). Histopathology of cerebral cortex and hippocampus, immunohistochemistry for tau- protein and caspase-3 with behavioral tests and measurement of several biochemical parameters were done. Hibiscus prevented memory impairment, and this could be attributed to the amelioration of STZ-induced neuroinflammation and amyloidogenesis. Consequently, Hibiscus represents a promising safe agent that can be repurposed for AD through exerting anti-inflammatory, anti-acetylcholinesterase, antioxidant, and anti-amyloidogenic activities.