Ischemic stroke (IS) progression is closely linked to neuroinflammation from microglial polarization imbalance. Its precise modulation, however, is limited by poor blood–brain barrier (BBB) penetration, low spatiotemporal accuracy, and systemic off-target effects. Nano drug delivery systems (NDDS) offer a promising alternative, utilizing enhanced BBB traversal and targeted lesion accumulation to address these challenges. Therefore, systematically sorting out the design strategies of NDDS targeting the regulation of microglia is of great significance for achieving precise treatment of ischemic stroke. This review outlines the pathophysiological mechanisms of IS and the biological characteristics of microglia, focusing on analyzing their dual regulatory roles in IS progression. Building upon this foundation, it explores NDDS strategies targeting microglial polarization, encompassing advanced delivery platforms such as liposomes and exosomes. Finally, future directions are proposed to advance NDDS-based therapeutic paradigms.