A dysregulated immune response is associated with an excessive release of cytokines that can lead to systemic vasoplegia and vasoplegic shock with the development of multiorgan failure that is associated with an increased risk of dying. Under physiological circumstances, the endothelium and the glycocalyx are responsible for maintaining vascular tone, capillary permeability, and hemostasis, and controlling inflammation. In hyperinflammation, the endothelium and glycocalyx become damaged due to the excessive production of certain toxic proteins, along with an overwhelming release of cytokines. It has been shown in both in vitro animal experiments and in humans that extracorporeal hemoadsorption can reduce circulating levels of cytokines and may also remove toxic proteins that directly take part in endothelium and glycocalyx damage. The current review aims to summarize current knowledge, put recent findings into context, and introduce the hypothesis of “endothelial protection with hemoadsorption” in critically ill patients.