SELENOK-dependent CD36 palmitoylation regulates microglial functions and Aβ phagocytosis. Selenium (Se) compounds show promise in Alzheimer's disease (AD) treatment. This study reveals that selenoprotein K (SELENOK), a selenoprotein involved in immune regulation and potentially related to AD pathology, 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, exacerbating 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 was reduced in the brains of patients and mice with AD. Se supplementation promoted 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 cytokines such as IL-1β, IL-6, TNF-α, and IL-10. SELENOK regulates microglial migration and phagocytosis, with reduced migration and phagocytic capacity in SELENOK knockout (SELK-KO) microglia. SELENOK promotes microglial phagocytosis and clearance of Aβ, with reduced Aβ phagocytosis in SELK-KO microglia. SELENOK knockout inhibits microglial Aβ phagocytosis and aggravates cognitive impairment in AD mice. SELENOK overexpression in microglia enhances Aβ phagocytosis and improves cognitive deficits in AD mice. SELENOK-dependent CD36 palmitoylation modulates microglial function and Aβ phagocytosis. SELENOK interacts with the ER-located palmitoyltransferase, DHHC6, enhancing its catalytic efficiency in palmitoylation. SELENOK regulates the post-translational modification, namely palmitoylation, of CD36 in microglia. These findings highlight the role of SELENOK in modulating microglial Aβ phagocytosis and AD progression, providing new insights into potential therapeutic strategies involving Se and selenoproteins.SELENOK-dependent CD36 palmitoylation regulates microglial functions and Aβ phagocytosis. Selenium (Se) compounds show promise in Alzheimer's disease (AD) treatment. This study reveals that selenoprotein K (SELENOK), a selenoprotein involved in immune regulation and potentially related to AD pathology, 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, exacerbating 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 was reduced in the brains of patients and mice with AD. Se supplementation promoted 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 cytokines such as IL-1β, IL-6, TNF-α, and IL-10. SELENOK regulates microglial migration and phagocytosis, with reduced migration and phagocytic capacity in SELENOK knockout (SELK-KO) microglia. SELENOK promotes microglial phagocytosis and clearance of Aβ, with reduced Aβ phagocytosis in SELK-KO microglia. SELENOK knockout inhibits microglial Aβ phagocytosis and aggravates cognitive impairment in AD mice. SELENOK overexpression in microglia enhances Aβ phagocytosis and improves cognitive deficits in AD mice. SELENOK-dependent CD36 palmitoylation modulates microglial function and Aβ phagocytosis. SELENOK interacts with the ER-located palmitoyltransferase, DHHC6, enhancing its catalytic efficiency in palmitoylation. SELENOK regulates the post-translational modification, namely palmitoylation, of CD36 in microglia. These findings highlight the role of SELENOK in modulating microglial Aβ phagocytosis and AD progression, providing new insights into potential therapeutic strategies involving Se and selenoproteins.