Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by memory loss and cognitive decline, where microglia activation triggers neuroinflammation, leading to neuronal damage. Shifting microglia polarization toward an anti-inflammatory phenotype may slow AD progression. Petunidin-3-O-(trans-p-coumaroylrutinoside)-5-O-glucoside (PtCG), the main anthocyanin in Lycium ruthenicum Murr., shows neuroprotective effects in AD mice, but its mechanism remains unclear.Purpose: The aim of this study was to investigate the protective effects of PtCG on APPswe/PS1ΔE9 transgenic mice and oAβ-induced BV2 cells and its mechanism.Methods: The effects of PtCG on cognitive function in APP/PS1 mice were evaluated using Morris water maze tests and Y-maze tests. AD-related markers were analyzed via brain pathology, Western blot, and ELISA. Hippocampal oxidative stress and inflammation were assessed, along with polarization-related proteins and the TREM2/DAP12/SYK pathway. BV2 microglia were used to confirm the impact of PtCG on neuroinflammation and polarization. Furthermore, molecular docking and cellular thermal shift assays (CETSA) were employed to analyze the binding interaction between PtCG and TREM2. Finally, key targets of PtCG were validated by knocking down TREM2 using TREM2 siRNA.Results: PtCG improved cognitive function and reduced AD pathology in APP/PS1 mice, decreasing Aβ deposition and Tau phosphorylation. It regulated microglia polarization by activating the TREM2/DAP12/SYK pathway, reducing oxidative stress and neuroinflammation while suppressing Iba1 expression. In oAβ-stimulated BV2 cells, PtCG similarly promoted an anti-inflammatory phenotype via TREM2/DAP12/SYK. Importantly, PtCG exerts this effect by directly binding to TREM2 to modulate microglial polarization and neuroinflammation. Furthermore, knockdown of TREM2 abrogated these effects, thus identifying TREM2 as an important molecular target for the anti-neuroinflammatory effects of PtCG.Conclusions: These results suggest that PtCG ameliorates AD-associated cognitive impairment by promoting anti-inflammatory microglial polarization via the TREM2/DAP12/SYK pathway. These findings reveal novel mechanistic details and validate TREM2 as a direct molecular target of PtCG in AD.