Objective and design Alzheimer's disease (AD) is associated with amyloid plaques (A beta) and hyperphosphorylated tau protein tangles in the brain. We investigated the possible neuroprotective role of flavocoxid, a dual inhibitor of cyclooxygenases-1/2 (COX-1/2) and 5-Lipoxygenase (5-LOX), in triple-transgenic (3xTg-AD) mice. Subjects Mice were 3 months at the beginning of the study. Treatment Animals received once daily for 3-month saline solution or flavocoxid (20 mg/kg/ip). Methods Morris water maze was used to assess learning and memory. Histology was performed to evidence A beta plaques and neuronal loss, while inflammatory proteins were determined by western blot analysis. Results Saline-treated 3xTg-AD mice showed an impairment in spatial learning and memory (assessed at 6 months of age), and increased expression of inflammatory and apoptotic molecules. Treatment of 3xTg-AD mice with flavocoxid reduced: (1) learning and memory loss; (2) the increased eicosanoid production and the phosphorylation level of amyloid precursor protein (APP-pThr668), A beta 1-42, p-tau (pThr181), pERK, and the activation of the NLRP3 inflammasome; (3) A beta plaques; and (4) neuronal loss, compared to saline-treated animals. Conclusions Pharmacological blockade of both COX-1/2 and 5-LOX was able to counteract the progression of AD by targeting pathophysiological mechanisms up- and downstream of A beta and tau.