To investigate the potential impact of platelet factor 4 (PF4) on the M1/M2 polarization of microglia in an Alzheimer's disease (AD) cell model and its possible molecular mechanisms. Methods: An AD cell model was induced by treating BV2 microglial cells with A β 1-42, followed by PF4 intervention. Furthermore, Trem2 expression was knocked down in BV2 cells through Trem2-siRNA transfection. Cell viability was assessed using the CCK8 assay; levels of TNF-α, IL-6, and IL-1β were measured by ELISA; the expressions of Trem2, iNOS, and Arg1 were detected via double-label immunofluorescence and Western blot analyses; mRNA levels of Trem2, iNOS, Arg1, TNF-α, and IL-10 were determined by RT-qPCR; and phagocytic function was evaluated using flow cytometry. Results: Compared with the control group, the A β 1-42 group exhibited significantly elevated expression levels of M1 phenotype markers (iNOS, TNF-α, IL-1 β) and IL-6, along with markedly decreased expression of M2 phenotype markers (Arg1, IL-10) and Trem2. In contrast, the (A β1-42+PF4) group showed reduced expression of M1 phenotype markers (iNOS, TNF-α, IL-1β) and IL-6, increased expression of M2 phenotype markers (Arg1, IL-10) and Trem2, and enhanced phagocytic capacity for A β 1-42 compared with the Aβ1-42 group. However, compared with the (Trem2-siRNA+Aβ1-42) group, PF4 failed to exert the aforementioned effects in BV2 cells in the (Trem2-siRNA+Aβ1-42+PF4) group. Conclusion: PF4 can regulate microglial polarization via Trem2, alleviate AD-related neuroinflammation, and promote the clearance of Aβ1-42.