Sepsis is a life-threatening organ dysfunction caused by an exacerbated inflammatory response to an infection. This multifactorial syndrome includes loss of hemodynamic coherence, increasing permeability and blood-brain-barrier breakdown, neuronal death, etc. The presence of cognitive deficits increases mortality. It is defined as sepsis-associated encephalopathy (SAE). Glial cells, such as astrocytes, and mostly the microglia, coordinate the immune response in the brain and are indispensable to SAE pathophysiology. This response occurs through cell signaling via cytokines, such as chemokine CCL21, initially described in the lymphoid system but also expressed by damaged neurons. This expression has been related to microglial recruitment and activation, although its role in sepsis remains incognito. Therefore, the present investigates the role of CCL21 in SAE. Using the cecal ligation and puncture (CLP) surgery model, we found in vivo that septic mice not only present higher levels of CCL21 expression but also its receptor CCR7 at the hippocampus and cerebral cortex. In vitro, we found that cortical neurons present higher CCL21 expression after 24h treatment with Lipopolysaccharide (LPS) whereas LPS-activated microglial cells express higher levels of CCR7 compared to not-activated ones. The CCL21 expressed by neurons increases microglial cell migration and adhesion. It also induces a shift in microglia morphology towards a more ameboid phenotype, indicating a more pro-inflammatory profile. Our data both in vitro and in vivo suggest that the CCL21/CCR7 pathway is essential to glial recruitment and activation in SAE.