BACKGROUND: Intracerebral hemorrhage (ICH) remains a devastating neurological disorder with limited therapeutic options. Neural stem cell (NSC)-based therapies have emerged as a potential regenerative approach, yet the molecular mechanisms regulating NSC behavior require further elucidation. The role of miR-21 in NSC differentiation and proliferation during ICH recovery remains unexplored. METHODS: In vitro NSC cultures were analyzed for miR-21 expression dynamics during differentiation via qPCR. Lentiviral overexpression and knockdown of miR-21 were employed to assess its functional impact. The SOX2/LIN28-let-7 pathway was investigated using Western blot, luciferase reporter assays, and immunofluorescence. In vivo, miR-21-overexpressing NSCs were transplanted into a murine ICH model, with neurogenesis evaluated by immunostaining and neurological recovery assessed through behavioral tests (mNSS, rotarod). RESULTS: miR-21 expression significantly increased during NSC differentiation, correlating with reduced SOX2 levels. Mechanistically, miR-21 directly targeted SOX2, disrupting the SOX2/LIN28-let-7 axis to promote NSC proliferation and lineage commitment. In ICH mice, transplantation of miR-21-overexpressing NSCs enhanced neurogenesis and improved motor coordination and neurological deficits at 28 days post-transplantation. CONCLUSIONS: Our findings identify miR-21 as a critical regulator of NSC plasticity through SOX2/LIN28-let-7 signaling, highlighting its therapeutic potential for enhancing neuroregeneration and functional recovery in ICH. Targeting miR-21 may represent a novel strategy to optimize NSC-based therapies for hemorrhagic stroke.