Multiple sclerosis (MS) is a disease that has inflammatory effects on the brain and spinal cord. Myelin sheath degradation is the prominent outcome of MS. This study is aimed to investigate protective effects of dietary fish oil in the form of ethyl esters (EE-FO) on demyelination in mice induced by cuprizone (CPZ). We found that EE-FO supplementation ameliorated CPZ-induced demyelination and improved learning and memory impairments of mice. It was observed that demyelination was alleviated in EE-FO-treated mice which was measured through luxol fast blue (LFB) staining and expression analyses of myelin basic protein (MBP). Additionally, it was also observed that activation of microglia in the corpus callosum was reduced in EE-FO treated mice. Furthermore, we demonstrated that EE-FO treatment down-regulated the expression of M1-markers, pro-inflammatory cytokine concentration i.e., TNF-α and IL-1β, and promoted M2-markers expression (CD206 and Arginase-1). Concomitantly, the EE-FO treatment showed an increased expression of SIRT1 and AKT but suppressed the expression of NF-κB p65 and NLRP3 inflammasomes in CPZ mice. Taken together, these results suggest that EE-FO supplementation exerts neuroprotective effects on demyelination in mice induced by CPZ by modulating the SIRT1/p-AKT and SIRT1/NF-κB/NLRP3 pathways.