Abstract Background Ischemia/reperfusion injury (I/R) is an important pathophysiology of post-cardiac arrest syndrome (PCAS) against multiple organ dysfunction and mortality. The inflammatory response in PCAS causes systemic I/R. The purpose of this study was to demonstrate the pathophysiology of systemic I/R for secondary brain damage using the biomarkers high-mobility group box 1 (HMGB1), neuron-specific enolase (NSE), and interleukin-6 (IL-6). Methods This study was designed as a single-institution prospective observational study. Subjects were observed for 90 days, and neurological outcome was classified according to the Glasgow-Pittsburgh Cerebral Performance Categories Scale (CPC). Serum HMGB1, NSE, and IL-6 were evaluated for variability, correlation with each biomarker, or the Sequential Organ Function Assessment (SOFA) score and CPC at return of spontaneous circulation at 0, 24, 48, and 168 h. Results A total of 128 patients were enrolled in this study. Initial HMGB1 correlated with CPC (ρ = 0.27, p = 0.036) and SOFA score (ρ = 0.33, p