Abstract The blood–brain barrier (BBB) is a highly selective membrane composed predominantly of brain capillary endothelial cells expressing drug efflux transporters that prevent substrates from accessing the brain. Inflammation is associated with central nervous system diseases and can impair BBB permeability via several mechanisms, including altered transporter and cell junction expression. This can modify the brain’s exposure to drugs. However, comprehensive genomic analysis of the impact of interleukin (IL)‐6, which plays a key role in the inflammatory response, on the BBB is lacking. In the present study, we analyzed the effects of exposure of hCMEC/D3 cells to 20 ng/mL IL‐6 for 72 h. We performed RNA sequencing and ABC transporter efflux assays. Physiologically based pharmacokinetics (PBPK) simulations were conducted to evaluate the potential impact of IL‐6 on the digoxin pharmacokinetics profile and brain exposure by decreasing BBB ABCB1 efflux activity. Exposure of hCMEC/D3 cells to IL‐6 triggered the deregulation of numerous genes involved in barrier permeability, such as cell junctions, focal adherens complex, and cell adhesion molecules. We observed mild modification of the mRNA expression and efflux activities of ABC transporters. PBPK simulation showed that, if we only consider the impact of IL‐6 on ABCB1 transporter, the modification of the digoxin pharmacokinetics profile and brain exposure is slight. IL‐6 slightly affected the gene expression levels and activities of ABC transporters on BBB cells, exhibiting a weaker effect than on hepatic cells. However, inflammation may cause other modifications, such as altered BBB permeability, that could modify drug pharmacokinetics.