Background High‐mobility group box 1 (HMGB1) is a major promotor of ischemic injuries and aseptic inflammatory responses. We tested its inhibition on neurological outcome and systemic immune response after cardiac arrest (CA) in rabbits. Methods and Results After 10 minutes of ventricular fibrillation, rabbits were resuscitated and received saline (control) or the HMGB1 inhibitor glycyrrhizin. A sham group underwent a similar procedure without CA. After resuscitation, glycyrrhizin blunted the successive rises in HMGB1, interleukin‐6, and interleukin‐10 blood levels as compared with control. Blood counts of the different immune cell populations were not different in glycyrrhizin versus control. After animal awakening, neurological outcome was improved by glycyrrhizin versus control, regarding both clinical recovery and histopathological damages. This was associated with reduced cerebral CD4 + and CD8 + T‐cell infiltration beginning 2 hours after CA. Conversely, granulocytes' attraction or loss of microglial cells or cerebral monocytes were not modified by glycyrrhizin after CA. These modifications were not related to the blood–brain barrier preservation with glycyrrhizin versus control. Interestingly, the specific blockade of the HMGB1 receptor for advanced glycation end products by FPS‐ZM1 recapitulated the neuroprotective effects of glycyrrhizin. Conclusions Our findings support that the early inhibition of HMGB1‐signaling pathway prevents cerebral chemoattraction of T cells and neurological sequelae after CA. Glycyrrhizin could become a clinically relevant therapeutic target in this situation.