<p>Our earlier research showed that deletion of tumor necrosis factor-α receptor II (TNFRII) exacerbated Alzheimer’s disease (AD) associated pathology in the AD mouse model. Previous studies have demonstrated that TNFRII was mainly expressed in astrocytes. However, whether AD-associated pathology can be modified by targeting TNFRII in astrocytes remains unknown. Here, we showed that TNFRII was decreased in astrocytes in AD brains. Then, we developed transgenic mouse models (astrocyte-specific expression of human TNFRII mice, TNFRII^GFAP mice) and crossed TNFRII^GFAP mice with a mouse model of AD (humanized APP knock-in mice, APP^NL-F/NL-F mice). We found that increased expression of TNFRII in astrocytes rescued learning and memory deficits, decreased amyloid burden, and reactive astrocytes in APP^NL-F/NL-F mice. Mechanistically, APP^NL-F/NL-F-TNFRII^GFAP mice displayed increased microgliosis, higher expression of plaque-associated microglial cluster of differentiation 68 (CD68), and enhanced microglial amyloid-β (Aβ) phagocytosis. <i>In vitro</i> assays confirmed that TNFRII upregulation in astrocytes enhanced phagocytosis of Aβ in BV2 murine microglial cell line (BV2) cells. Our study implicates that increased expression of TNFRII in astrocytes ameliorates pathology and behavioral deficits in APP^NL-F/NL-F mice and provides new therapeutic options for AD.</p>