Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. Accumulating experimental evidence shows the important role of tumor necrosis factor-α (TNF-α) signaling in AD, but the exact role of TNF-α in AD is still not completely understood. Although TNF-inhibitors are successfully used for treatment of several autoimmune diseases, like rheumatoid arthritis, total inhibition of TNF-α can cause adverse side effects in neurological diseases. This is attributed to the opposing roles of the two receptors of TNF-α. TNF receptor 1 (TNFR1) predominantly mediates inflammatory and pro-apoptotic signaling pathways, whereas TNF receptor 2 (TNFR2) is related to neuroprotection and promotes tissue regeneration. Thus, the specific activation of TNFR2 signaling seems a promising strategy for AD therapy. Our approach consists on treating an APP overexpressing AD mouse with a specific TNFR2 agonist to investigate its effectiveness in AD-related pathology. Treated and control animals were evaluated in behavioral tests and neuropathological changes were investigated. Our results showed that administration of the TNFR2 agonist resulted in a drastic reduction of Aβ plaques and beta-secretase 1 (BACE-1). Moreover, we observed an increase in microglial activation and phagocytosis, which may be related to a higher clearance rate of Aβ. Finally, at the behavioral level, our treatment showed an improvement in cognitive functions. Altogether, these results suggest that activation of TNFR2 might be useful as a potential treatment for AD.