<p>Ischaemic stroke is the leading cause of long-term cognitive impairments, affecting brain regions vulnerable to memory and learning, with complex and diverse mechanisms. The hippocampus along with cortex is crucial for shaping essential cognitive functions in post-stroke cognitive impairments. However, the region-specific neural, molecular and cellular mechanistic response to ischaemic-damage, particularly the role of inflammation is rarely explored. In this context, we carried out post-stroke region-specific research, including the development of BCCAo model and the neurobehavioral assessment targeting memory and learning deficits. Here, we performed NGS and depth-in-network analysis of the isolated cortical and hippocampal regions of the post-stroke BCCAo model, revealing 13 significant neurodegenerative hub genes including <i>Map2k6</i> and <i>Mapk11</i>, which play crucial roles in inflammation-mediated post-stroke neurodegenerative cascades. Significant upregulation of <i>Map2k6/Mapk11</i> in the cortex of <i>ischaemic</i> rats was observed, whereas its comparatively diminished expression in the hippocampus demand exploration of region-specific study in chronic ischaemic conditions. Furthermore, we demonstrated the role of MAPK11 as neuroinflammatory regulator and alleviating the cognitive impairments by including the upstream Akt/GSK3β pathway components. Our findings not only highlighted the potential roles of <i>Map2k6/Mapk11</i> driving neuroinflammatory processes regulating ischaemic cascades but also pinpointed the hippocampus’s relative resilience preserving cognitive function. Targeting MAPK11 and its associated neuroinflammatory pathways in the cortex to mitigate post-stroke cognitive impairments (PSCI) holds promise as a therapeutic strategy in chronic ischaemia. </p> Graphical Abstract <p></p>