<p>The subiculum contains functionally distinct dorsal and ventral subdivisions and is implicated in temporal lobe epilepsy (TLE). Yet, the contribution of ventral subicular glutamatergic neurons (vSub^glu) to epileptogenesis remains unclear. Using in vivo fiber photometry and c-Fos mapping in a hippocampal-kindling TLE model, we identified pronounced hyperactivation of vSub^glu during seizure development. Optogenetic activation of vSub^glu alone recapitulated the kindling process and accelerated kindling progression when applied following electrical stimulation. Conversely, optogenetic or chemogenetic inhibition of vSub^glu robustly suppressed seizure development in both the kindling model and the acute KA model and delayed epileptogenesis in the chronic KA model. Circuit-specfic manipulations revealed that the pro-epileptic effects are mediated predominantly through glutamatergic projections from the vSub to the anterior thalamic glutamatergic neurons (ATN^glu). This vSub^glu-ATN^glu circuit exhibited both necessity and sufficiency for epileptogenesis in the kindling model, as evidenced by pathway-specific manipulations. Collectively, our findings uncover a previously unrecognized hippocampo–thalamic circuit that critically governs epileptogenesis in TLE, highlighting vSub^glu-ATN^glu circuit as a promising target for TLE therapeutic intervention.</p>