<p>Traumatic brain injury (TBI) induces not only local neuroinflammation but also systemic immune responses involving peripheral organs such as the spleen. While synaptamide (N-docosahexaenoylethanolamine), an endogenous lipid mediator derived from docosahexaenoic acid, has demonstrated neuroprotective effects, its impact on peripheral immune regulation after TBI remains unclear. In this study, we investigated the anti-inflammatory effects of synaptamide in a murine weight-drop TBI model. Male C57BL/6 mice were divided into five groups: “Control”, “Sham” (craniotomy only), “Sham + Syn” - craniotomy with synaptamide treatment, “TBI”, and TBI with synaptamide treatment. Synaptamide (10 mg/kg) was administered subcutaneously immediately after injury and then daily for 6 days. On day 7 post-TBI, analysis revealed that synaptamide significantly reduced proinflammatory cytokine levels in both serum (IL-1β by 23% (p &lt; 0.05), IL-6 by 23% (p &lt; 0.01), and TNF-α by 15% (p &lt; 0.05)) and spleen tissue (IL-1β by 37% (p &lt; 0.001), IL-6 by 30% (p &lt; 0.001), and TNF-α by 34% (p &lt; 0.01)) compared to untreated TBI animals. Histological evaluation exhibited synaptamide treatment decreased Iba-1-positive macrophage infiltration in the spleen by 36% and restored the white/red pulp ratio to near-normal levels (0.69 in the “TBI” group vs. 0.39 in the “TBI + Syn” group (p &lt; 0.001)).These findings demonstrate that synaptamide exerts anti-inflammatory effects in the peripheral immune system following TBI, particularly through modulation of splenic macrophage activity and cytokine production. The results support synaptamide potential as a dual-action therapeutic agent capable of addressing both central and peripheral inflammatory responses after TBI. </p>