The transcription factor Nrf2 (encoded by the Nfe2l2 gene) is a widely-expressed stress-responsive master regulator of several aspects of homeostatic physiology. Nrf2 plays a key role in preventing oxidative stress and inflammation. In the brain, Nrf2 is highly expressed by endothelial cells. Brain endothelial cells (BECs) are the key component of the blood brain barrier (BBB), which controls brain homeostasis. The role of BEC Nrf2 expression in maintaining homeostasis is not fully understood. In this project, through gain- and loss function experiments, we have found that Nrf2 activity in BECs regulates barrier strength in vitro. We have generated inducible endothelial cell specific Nrf2 knockout mice, which showed that basal Nrf2 activity controls key transcriptional signatures in BECs in vivo. Administration of RTA-404, a potent Nrf2 activator, strongly affected the BEC transcriptomic changes that occur in response to a peripheral inflammatory stimulus (LPS). The effect of RTA-404 on BEC responses to LPS is abolished in an EC-specific Nrf2 KO mice. LPS administration also causes neuroinflammation including astrogliosis, which can be suppressed by RTA-404. Strikingly, this anti-inflammatory effect of RTA-404 on astrocyte responses is abolished in EC-specific Nrf2 KO mice. These experiments provide proof-of-concept that BEC Nrf2 can act as a key upstream regulator of trans-BBB inflammatory signalling.