Dystrophic neurites and activated microglia are one of the main neuropathological characteristics of Alzheimer's disease (AD). Although the use of supplements with omega-3 fatty acids has been associated with reduced risk and lessened AD pathology, it still remains elusive whether such a treatment could affect dystrophic neurites (DNs) formation and microglia/macrophage behavior in the early phase of disease. We analyzed the effects of short-term (3 weeks) fish oil supplementation on DNs formation, tau hyperphosphorylation, Amyloid-beta peptide 1-42 (Aβ42) levels and microglial/macrophage response to AD pathology in the parietal cortex of 4-month-old 5xFAD mice, a mouse model of AD. The present study shows for the first time that short-term FO supplementation applied in presymptomatic stage of AD, alters the behaviour of microglia/macrophages prompting them to establish a physical barrier around amyloid plaques. This barrier significantly suppresses DNs formation through the reduction of both Aβ content and tau hyperphosphorylation. Moreover, the short-term FO treatment neither suppresses inflammation nor enhances phagocytic properties of microglia/macrophages in the response to Aβ pathology, the effects most commonly attributed to the fish oil supplementation. Our findings suggest that fish oil consumption may play an important role in modulating microglial/macrophage response and ameliorating the AD pathology in presymptomatic stage of Alzheimer's disease.