Cigarette smoke comprises nicotine, reactive oxygen species (ROS), and carcinogens, which can induce oxidative stress and inflammation, leading to disruption of the blood-brain barrier. This study utilized cigarette smoke extract (CSE) in an in vitro model of the blood-brain barrier (BBB).Sesamol is a phenolic compound derived from Sesamum indicum L. Its potential to reduce inflammation and provide protection was also examined. As a result of the study, it was found that CSE significantly increases permeability by degrading the BBB, whereas a protective effect was observed in the sesamol-incubated group within the BBB model. While the Sesamol + CSE group does not entirely prevent the damage induced by CSE in the barrier, it does exhibit a mitigating effect on the damage.In HUVEC cells, a significant decrease in IL-8 levels was observed in sesamol and sesamol + CSE groups. In T98G cells, IL-8 levels were elevated in the CSE group, while a reduction was observed in the sesamol and sesamol + CSE groups. TNF-α levels went up in the CSE group but down in the sesamol and sesamol + CSE groups in T98G cells. Furthermore, the IL-6 levels were significantly increased in both the sesamol and sesamol + CSE groups in HUVEC cells, while a decrease was noted in T98G cells in sesamol treatment. The increase in IL-8 and TNF-α levels in T98G cells due to CSE indicates an inflammatory response. It can contribute to the enhanced BBB permeability. As a result, sesamol reduced inflammation caused by CSE by controlling IL-8, IL-6, and TNF-α. This molecule may serve a therapeutic role by diminishing inflammation and protecting the blood-brain barrier from damage.