Alterations along the brain-gut axis participate in the pathogenesis of neurodegenerative diseases. Recent data suggest that the gut microbiota partially exerts its action by modulating neuroinflammation. Interestingly, neuroinflammation has been postulated as one of the leading causes of Alzheimer’s Disease (AD). Therefore, targeting brain inflammation has been suggested as a promising therapeutic strategy to cope with AD. In this regard, neuroinflammation has been related to the soluble epoxide hydrolase (sEH) enzyme, which is upregulated in the brains of AD patients and mice models of AD. Considering this, its inhibition would be beneficial to stop neuroinflammation and promote a positive outcome in AD.We tested a new and selective inhibitor of sEH capable of crossing the blood-brain barrier, called UB-BJ-02. Firstly, UB-BJ-02 caused significant changes in gut microbiota and attenuated colon and plasma proinflammatory markers in the 5XFAD mouse model. In addition, behavioral tasks (NORT and OLT) demonstrated that UB-BJ-02 improves short- and long-term memory and spatial memory in the 5XFAD. Secondly, we found a reduction of neuroinflammatory markers evaluated by gene expression in the brain of 5XFAD-treated mice and a significant decrease in the number of Aβ plaques. Finally, we also explored mitochondrial dysfunction, which is altered in AD pathological cascade, and we found a decrease in mitochondrial fission and an increase in the fusion process, leading to better mitochondrial activity after sEH inhibition. Overall, the present study suggested that sEH inhibition with UB-BJ-02 promoted neuroprotective effects by modulating gut microbiota and subsequently modifying peripheric and brain proinflammatory markers.