COVID‐19 is associated with encephalitis in critically ill patients and endothelial dysfunction seems to contribute to this life‐threatening complication. Our objective was to determine the hallmark of endothelial activation in COVID‐19‐related encephalitis. In an observational study in intensive care unit (ICU), we compared vascular biomarkers of critically ill COVID‐19 patients with or without encephalitis. To be classified in the encephalitis group, patients had to have new onset of central neurologic symptom, and pathological findings on either brain magnetic resonance imaging (MRI) and/or electroencephalogram (EEG). Among the 32 critically ill COVID‐19 consecutive patients, 21 were categorized in the control group and 11 in the encephalitis group. Encephalitis patients had a longer ICU stay than control patients (median length 25th–75th percentile of 52 16–79 vs. 20.5 11–44 days, respectively, p = 0.04). Nine‐month overall follow‐up mortality reached 21% (7/32 patients), with mortality rates in the encephalitis group and the control group of 27% and 19%, respectively. Encephalitis was associated with significant higher release of soluble endothelial activation markers (sE‐selectin, tumor necrosis factor‐α (TNF‐α), interleukin 6, placental growth factor, and thrombomodulin), but these increases were correlated with TNF‐α plasmatic levels. The hypoxia‐inducible protein angiopoietin‐like 4 (ANGPTL4) was at significantly higher levels in encephalitis patients compared to control patients (p = 0.0099), and in contrary to the other increased factors, was not correlated with TNF‐α levels (r = 0.2832, p = 0.1163). Our findings suggest that COVID‐19‐related encephalitis is a cytokine‐associated acute brain dysfunction. ANGPTL4 was the only elevated marker found in encephalitis patients, which was not correlated with systemic inflammation, suggesting that ANGPTL4 might be a relevant factor to predict encephalitis in critically ill COVID‐19 patients. COVID‐19 is associated with encephalitis in critically ill patients with acute respiratory distress syndrome (ARDS). Endothelial dysfunction contributes to this complication. Our findings suggest that COVID‐19‐related encephalitis in critically ill patients is consecutive to the systemic inflammation following ARDS. This inflammation leads to an endothelial cell dysfunction through the increase in cell surface adhesion molecules expression, brain endothelial cell permeability, and coagulation dysregulation. However, angiopoietin‐like 4 (ANGPTL4), a secreted glycoprotein, was the only elevated marker found in encephalitis patients, which was not correlated with systemic inflammation. ANGPTL4 role (cause or consequence) in COVID‐19 encephalitis remains to be determined.