Background: Endothelial dysfunction is implicated in various inflammatory diseases such as ischemic stroke, heart attack, organ failure, and COVID-19. Recent studies have shown that endothelial dysfunction in the brain is attributed to excessive inflammatory responses caused by the SARS-CoV-2 infection, leading to increased permeability of the blood-brain barrier and consequently neurological damage. Here, we aim to examine the single-cell transcriptomic landscape of endothelial dysfunction in COVID-19 and its implications for glioblastoma (GBM) progression. Methods: Single-cell transcriptome data GSE131928 and GSE159812 were obtained from the gene expression omnibus (GEO) to analyze the expression profiles of key players in innate immunity and inflammation between brain endothelial dysfunction caused by COVID-19 and GBM progression. Results: Single-cell transcriptomic analysis of the brain of COVID-19 patients revealed that endothelial cells had undergone significant transcriptomic changes, with several genes involved in immune responses and inflammation upregulated. Moreover, transcription factors were observed to modulate this inflammation, including interferon-regulated genes. Conclusions: The results indicate a significant overlap between COVID-19 and GBM in the context of endothelial dysfunction, suggesting that there may be an endothelial dysfunction link connecting severe SARS-CoV-2 infection in the brain to GBM progression.