Synaptic dysfunction is one of the most important markers of neurodegenerative diseases, which contribute to cognitive decline and the loss of neurons. Synaptosomal-associated protein 25 (SNAP-25) is a member of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, which plays a significant role in the exocytosis of synaptic vesicles and the release of neurotransmitters. Recent studies have shown that expression levels of SNAP-25 are altered in various neurodegenerative disorders, including Alzheimer's disease (AD), Huntington's disease (HD), and Creutzfeldt-Jakob disease (CJD). These investigations led to the consideration of SNAP-25 as a potential biomarker of synaptic degeneration. Understanding the role of SNAP-25 in neurodegeneration will aid in early diagnosis, disease monitoring, and therapeutic development, and will also provide new insights into synaptic dysfunction as a main feature of neurodegenerative diseases. Therefore, this paper explores the physiological role of SNAP-25, its involvement in synaptic pathology, and the implications of its dysregulation in neurodegenerative conditions, such as AD, HD, and CJD. Literature regarding cerebrospinal fluid (CSF) SNAP-25 levels as a diagnostic marker were reviewed and its applications in detecting the progression of the disease have been discussed. Additionally, the limitations of SNAP-25 as a biomarker, including variability across studies and the need for further validation have been addressed.