<p>Neurological diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and epilepsy constitute a major global public health burden, affecting millions of patients. Recent studies have shown that the complex interactions between the immune system and the nervous system play a significant role in these diseases, especially Toll-like receptors (TLRs), among which endosomal TLRs (TLR3, TLR7, TLR8, and TLR9) are crucial in neuroinflammation and disease progression. This review systematically elaborates on the biological characteristics of endosomal TLRs, their distribution, and signaling pathways within the central nervous system, with a particular focus on their “double-edged sword” effect in specific disease contexts: on the one hand, they may provide neuroprotection, while on the other hand, they can exacerbate neural injury and neurodegeneration during immune dysregulation. Furthermore, this article evaluates the potential and challenges of utilizing endosomal TLRs as early diagnostic biomarkers. It summarizes research progress in targeted regulatory strategies as emerging therapeutic approaches, along with the encountered bottlenecks in clinical translation. The review aims to systematically integrate fundamental mechanistic research with clinical application prospects, emphasizing the critical importance of in-depth elucidation of the mechanistic roles of endosomal TLRs in neurological disorders and their translational value in diagnosis and treatment. Clinical trial number: not applicable.</p> Graphical Abstract