Neuroinflammation is an important risk factor for neurodegenerative disorders like Alzheimer's disease. Nicotinic acetylcholine receptors of α7 subtype (α7 nAChRs) regulate inflammatory processes in various tissues, including the brain. N-stearoylethanolamine (NSE) is a biologically active cell membrane component with anti-inflammatory and membrane-protective properties. Previously we found that mice injected with bacterial lipopolysaccharide (LPS) or immunized with recombinant extracellular domain (1–208) of α7 nAChR subunit possessed decreased α7 nAChR levels, accumulated pathogenic amyloid-beta peptide Aβ(1–42) in the brain and demonstrated impaired episodic memory compared to non-treated mice. Here we studied the effect of NSE on behavior and brain components of LPS- treated or α7(1–208)-immunized mice. NSE, given per os, non-significantly decreased LPS-stimulated interleukin-6 elevation in the brain, slowed down the α7(1–208)-specific IgG antibody production and prevented the antibody penetration into the brain of mice. NSE prevented the loss of α7 nAChRs and accumulation of α7-bound Aβ(1–42) in the brain and brain mitochondria of LPS-treated or α7(1–208)-immunized mice and supported mitochondria resistance to apoptosis by attenuating Ca2 +-stimulated cytochrome c release. Finally, NSE significantly improved episodic memory of mice impaired by either LPS treatment or immunization with α7(1–208). The results of our study demonstrate a therapeutic potential of NSE for prevention of cognitive disfunction caused by neuroinflammation or autoimmune reaction that allows suggesting this drug as a candidate for the treatment or prophylaxis of Alzheimer's pathology.