Aim: A recent trial did not demonstrate a significant relationship between interleukin 6 (IL-6) and neuronal injury, such as neuron-specific enolase (NSE). However, it is a well-understood concept throughout medicine that treatment effects depend on injury or disease severity. We hypothesize that IL-6 is independently associated with NSE according to cardiac arrest severity. Thus, this study aimed to investigate the relationship of IL-6 with NSE during post-resuscitation care according to cardiac arrest severity. Methods: This retrospective study included patients who underwent post-resuscitation care. IL-6 and NSE were measured at 0, 24, 48, and 72 h immediately after applying the temperature control device. We divided the cohort into three groups of low, moderate, and severe severity based on the “Revised Post-Cardiac Arrest Syndrome for Therapeutic Hypothermia” scoring system. Stepwise linear regression was performed to analyze the correlation of the entire IL-6 measured at all times with the inflammatory, myocardial injury, and neuronal injury markers to account for other covariables. Results: Of the 111 enrolled patients, 22, 59, and 28 were in low, moderate, and severe severity groups, respectively. Median IL-6 and NSE were significantly different between groups (IL-6, 145.2 pg/mL vs. 949.7 pg/mL vs. 1100.7 pg/mL, p = 0.001; NSE, 24.4 ng/mL vs. 48.7 ng/mL vs. 63.2 ng/mL, p = 0.001). Stepwise linear regression analysis revealed that the IL-6 did not significantly correlate with other markers in low severity groups (F = 2.38, p = 0.13); however, in the severe severity group, IL-6 was independently correlated with NSE in severe severity groups (β = 8.16, p = 0.001). Conclusion: IL-6 level was associated with cardiac arrest severity. IL-6 was independently correlated with NSE in the severe severity group but not in low to moderate severity groups. Therefore, the correlation between IL-6 and neuronal injury markers may be dependent on the cardiac arrest severity.