Background and Purpose Alzheimer’s disease (AD), a progressive neurological disorder that causes memory decline and cognitive dysfunction, increasingly threatens human health. Rehmanniae Radix Praeparata (RRP) is derived from the steamed or wine-steamed Scrophulariaceae plant, Rehmannia glutinosa Libosch. (RR). They show promise in the treatment of AD, yet the variations in medical components and their mechanisms of action against AD remain unclear. Experimental Approach This study initially used APP/PS1 mice as AD animal models and used UPLC-QE-MS/MS, network pharmacology, proteomics, 16S rRNA sequencing to investigate differences in the medical components and mechanisms of action of RR and RRP in treating AD. Results UPLC-QE-MS/MS screening revealed that ajugol was the effective medicinal component of RR for AD treatment, and isoacteoside was that of RRP. Integrated multi-omics analyses predicted the involvement of the neuroinflammatory pathway, apoptosis pathway, and autophagy pathway in the mechanisms of the two ingredients for AD treatment. Subsequent in vivo and in vitro experiments confirmed that RR and its active component, ajugol, primarily modulated TLR/NF-κB/NLRP3 neuroinflammatory pathway and Bcl-2/Bax/Cytochrome C/Caspase-3 apoptosis pathway, whereas RRP and its active component isoacteoside predominantly affected LC3-Ⅱ/P62/p-mTOR/mTOR autophagy pathway. These components collectively improved cognitive deficits in AD mice, reduced Aβ plaque deposition in brain tissue, and diminished BV2 microglial cell cytotoxicity in the inflammation model, thereby ameliorating the progression of AD. Conclusion This study systematically elucidated the distinctions in the medical components and biological mechanisms of RR and RRP in treating AD, revealing that the unique processing of TCM is key to its efficacy.