SELENOK-dependent CD36 palmitoylation regulates microglial functions and Aβ phagocytosis. Selenium (Se) compounds show promise in Alzheimer's disease (AD) treatment, and selenoprotein K (SELENOK) plays a critical role in microglial immune response, migration, and phagocytosis. In vivo and in vitro studies show that SELENOK deficiency inhibits microglial Aβ phagocytosis, worsening cognitive deficits in 5xFAD mice, which are reversed by SELENOK overexpression. Mechanistically, SELENOK is involved in CD36 palmitoylation through DHHC6, regulating CD36 localization to microglial plasma membranes and thus impacting Aβ phagocytosis. CD36 palmitoylation is reduced in AD patients and mice, while Se supplementation promotes SELENOK expression and CD36 palmitoylation, enhancing microglial Aβ phagocytosis and mitigating AD progression. The study identifies the regulatory mechanisms from Se-dependent selenoproteins to Aβ pathology, providing novel insights into potential therapeutic strategies involving Se and selenoproteins. SELENOK depletion impairs microglial immune response, reducing inflammatory cytokine levels and affecting microglial migration and phagocytosis. SELENOK overexpression enhances microglial phagocytosis and Aβ clearance, improving cognitive deficits in AD mice. SELENOK-dependent CD36 palmitoylation modulates microglial function and Aβ phagocytosis, with SELENOK interacting with DHHC6 to regulate CD36 palmitoylation. These findings highlight the importance of SELENOK in maintaining microglial immune homeostasis and Aβ clearance in AD.SELENOK-dependent CD36 palmitoylation regulates microglial functions and Aβ phagocytosis. Selenium (Se) compounds show promise in Alzheimer's disease (AD) treatment, and selenoprotein K (SELENOK) plays a critical role in microglial immune response, migration, and phagocytosis. In vivo and in vitro studies show that SELENOK deficiency inhibits microglial Aβ phagocytosis, worsening cognitive deficits in 5xFAD mice, which are reversed by SELENOK overexpression. Mechanistically, SELENOK is involved in CD36 palmitoylation through DHHC6, regulating CD36 localization to microglial plasma membranes and thus impacting Aβ phagocytosis. CD36 palmitoylation is reduced in AD patients and mice, while Se supplementation promotes SELENOK expression and CD36 palmitoylation, enhancing microglial Aβ phagocytosis and mitigating AD progression. The study identifies the regulatory mechanisms from Se-dependent selenoproteins to Aβ pathology, providing novel insights into potential therapeutic strategies involving Se and selenoproteins. SELENOK depletion impairs microglial immune response, reducing inflammatory cytokine levels and affecting microglial migration and phagocytosis. SELENOK overexpression enhances microglial phagocytosis and Aβ clearance, improving cognitive deficits in AD mice. SELENOK-dependent CD36 palmitoylation modulates microglial function and Aβ phagocytosis, with SELENOK interacting with DHHC6 to regulate CD36 palmitoylation. These findings highlight the importance of SELENOK in maintaining microglial immune homeostasis and Aβ clearance in AD.