Background <p>Alzheimer’s disease (AD) is a progressive neurodegenerative disorder predominantly affecting the elderly population. It is characterized by cognitive deficits associated with the accumulation of amyloid-beta plaques and neurofibrillary tangles. Huang-Lian-Jie-Du (HLJD) decoction, recognized as a representative formulation with heat-clearing and detoxification effects, has been demonstrated to be effective in treating AD. However, the underlying mechanisms require further investigation.</p> Methods <p>5xFAD mice were administrated low and high doses of HLJD. The Morris water maze test was conducted to assess the effects of HLJD. Aβ42 and total tau protein levels were evaluated. Additionally, network pharmacology analysis was performed to identify therapeutic targets of HLJD’s active components and their relevance to AD. ELISA, qPCR, Western Blot, and immunofluorescence assays were employed to confirm the identified pathways. Finally, primary microglia isolated from 5xFAD mice were used to validate the candidate targets of HLJD.</p> Results <p>HLJD improved cognitive deficits in 5xFAD mice and reduced amyloid plaque deposition and tau protein levels. Network pharmacology analysis indicated that HLJD influences the neuroinflammatory response, particularly through the Dap12 signaling pathway. This was confirmed by reduced levels of neuroinflammation markers, including TNF-α, IL-1β, IL-6, and indicators of microglial activation and polarization. The expression of Trem2 and Dap12 in the hippocampus (HIP) of 5xFAD mice, as well as in the isolated primary microglia, were downregulated following HLJD treatment.</p> Conclusion <p>Our study indicates that HLJD alleviates cognitive deficits in AD by suppressing the Trem2/Dap12 signaling pathway in the HIP of 5xFAD mice, thereby inhibiting microglial neuroinflammation.</p> Graphical Abstract <p></p>