Structural, electrical, and metabolic alterations in the brain characterize neurodegenerative illnesses, which include Parkinson’s disease (PD), Huntington’s disease (HD), Tardive Dyskinesia (TD), epilepsy, Alzheimer’s disease (AD), and schizophrenia. Five distinct phosphoproteins make up the family of cytosolic proteins known as collapsin response mediator proteins (CRMPs), which are significantly produced throughout the nervous system’s development phase. This implies that CRMPs play a crucial part in directing the proliferation of neurons and the formation of axons. These proteins come in two varieties, one shorter (65 kDa) and the other longer (80 kDa) with N-terminal extensions. They are encoded by five different genes. Increased CRMP expression during central nervous system development is linked to several signaling networks, including the Rho Kinase pathway, glycogen synthase kinase-3 (GSK-3), and cyclin-dependent kinase 5 (CDK-5). These signaling pathways’ hyperphosphorylation of CRMP-2 under pathological circumstances leads to neurodegeneration in a number of neurological diseases. In neurodegenerative illnesses, phosphorylated versions of CRMP-2 impair neuronal polarity and limit axonal development, whereas unphosphorylated forms stimulate microtubule assembly and axonal growth. The focus of this review is on investigating the therapeutic effectiveness of CRMP-2 modulation in the treatment of different neurodegenerative diseases.