Rheumatoid arthritis (RA) is a chronic condition characterized by pain and infiltration of immune cells into the joint. Immune cells can be activated, producing inflammatory cytokines, leading to continuously degenerative and inflammatory reactions and the temporomandibular joint (TMJ) can be affected by RA. In this scenario, novel targets are needed to increase treatment efficacy with minimized side effects. The epoxy-eicosatrienoic acids (EETs), are endogenous signaling molecules, playing important roles in diminishing inflammation and pain but are promptly metabolized by soluble epoxide hydrolase (sEH), generating less-bioactive acids.Therefore, sEH inhibitors is an interest therapeutic target to enhance the beneficial effect of natural EETs. TPPU is a potent sEH inhibitor that is capable of dampening EETs hydrolysis. Thus, we aimed to assess the impact of pharmacological sEH inhibition on a persistent model of albumin-induced arthritis in the TMJ, in two scenarios: first, as post-treatment, in an installed arthritic condition, and second, the protective role, in preventing the development of an arthritic condition. In addition, we investigate the influence of sEH inhibition on microglia cell activation in the trigeminal subnucleus caudalis (TSC) and in vitro experiments. Finally, we examined the astrocyte phenotype. Oral administration of TPPU, acts in multiple pathways, in a protective and reparative post-treatment, ameliorating the preservation of the TMJ morphology, reducing the hypernociception, with an immunosuppressive action reducing neutrophil and lymphocytes and pro-inflammatory cytokines in the TMJ of rats. In TSC, TPPU reduces the cytokine storm and attenuates the microglia activated P2X7/Cathepsin S/Fractalkine pathway and reduces the astrocyte activation and glutamate levels. Collectively, our findings revealed that sEH inhibition mitigates hypersensitive nociception through the regulation of microglia activation and astrocyte modulation, demonstrating the potential use of sEH inhibitors as immunoresolvents in the treatment of autoimmune disorders.