<p>Neural stem cells (NSCs) persist throughout adulthood and contribute to circuit maintenance through controlled neurogenesis and trophic, metabolic, and immunomodulatory signaling. However, across neurological and psychiatric disorders, NSCs are not passive bystanders but direct targets of disease pathology and active participants in its progression. Evidence from stroke, Alzheimer’s disease, Parkinson’s disease, epilepsy, depression, anxiety, bipolar disorder, autism spectrum disorder, and schizophrenia shows that pathogenic conditions, such as neuroinflammation, oxidative and metabolic stress, and hypothalamic–pituitary–adrenal axis dysregulation disrupt intrinsic NSC programs. These insults suppress NSC activation, impair lineage commitment, and alter the NSC secretome in ways that exacerbate synaptic dysfunction and network instability. Despite interest in NSC-based transplantation, structural replacement remains constrained by poor survival, migration, long-range integration, and safety considerations. In contrast, paracrine mechanisms and extracellular vesicles drive more consistent functional benefits by suppressing neuroinflammation, protecting vulnerable neurons, restoring neurovascular integrity, and modulating immune and metabolic homeostasis. NSCs with gene editing, bioengineered scaffolds, extracellular matrix-mimetic hydrogels, and exosome-based delivery offer renewed translational potential. By repositioning NSCs as both vulnerable targets and mechanistic drivers of disease rather than secondary responders, this review reframes shared pathological processes across brain disorders and highlights NSCs as a tractable entry point for therapeutic intervention and circuit repair.</p>