<p>The development of drugs for mesial temporal lobe epilepsy (mTLE) is hampered by the absence of preclinical models that can concurrently evaluate blood-brain barrier (BBB) penetration and target efficacy. To bridge critical gaps in preclinical screening, we developed an integrated microfluidic µBBB-(KA-MG)-mTLE chip that simultaneously models a perfusable human BBB under physiological shear stress (0.03–2.04 dyn/cm²) and a neuroinflammatory mTLE microenvironment with activated microglia. This platform enabled the dual-parameter assessment of drug candidates, quantifying their BBB permeability and anti-inflammatory activity in a single experiment. In a practical screening application, osthole was identified as a promising candidate for its adequate brain exposure and potent efficacy, whereas a high molecular weight grape seed extract showed activity only when bypassing the BBB, demonstrating the platform’s critical ability to de-risk candidate selection. Our biomimetic system provides a transformative tool for anti-epileptic drug discovery by integrating pharmacokinetic and pharmacodynamic evaluation.</p> Graphical Abstract <p></p>