Endotheliopathy plays a role in the development of acute kidney and lung injury in COVID-19, probably due to inflammation, endothelial permeability, vascular leakage and edema formation. This study examined alterations in the circulation of patients with mild and severe COVID-19 on in vitro endothelial permeability and its relation to the endothelial angiopoietin/Tie2 system, which is involved in the regulation of endothelial permeability. Plasma was obtained from COVID-19 patients admitted to the ward (n = 14) or ICU (n = 20) at admission and after 1 and 2 weeks and healthy controls (n = 5). Human kidney and lung endothelial cells were exposed to patient plasma and treated with recombinant angiopoietin-1. In vitro endothelial barrier function was assessed using electric cell-substrate impedance sensing. Circulating markers of the angiopoietin/Tie2 system, endothelial dysfunction and glycocalyx degradation were measured by ELISA. Plasma from COVID-19 patients reduced endothelial resistance compared to healthy controls, but COVID-19 plasma-induced drop in endothelial resistance did not differ between ward and ICU patients. Circulating angiopoietin-2, soluble Tie2 and soluble Tie1 levels increased over time in ICU patients, whereas levels remained stable in ward patients. The increase in angiopoietin-2 was able to predict 90-day mortality (AUC = 0.914, p < 0.001). Treatment with recombinant angiopoietin-1 did not restore COVID-19 plasma-induced hyperpermeability. In conclusion, these results suggest that indirect effects of the virus represented in the circulation of COVID-19 patients induced endothelial hyperpermeability irrespective of disease severity and changes in the endothelial angiopoietin/Tie2 system. Nonetheless, angiopoietin-2 might be of interest in the context of organ injury and patient outcome in COVID-19.