Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by progressive demyelination and neuroinflammation, leading to axonal damage and neuronal degeneration. It is the most prevalent non-traumatic cause of neurological disability in young adults, affecting millions of people worldwide. MS manifests with a wide range of symptoms, including motor dysfunction, sensory deficits, and cognitive impairment, which can severely impact the quality of life. Despite extensive research, the exact pathogenesis of MS remains unclear, and currently available treatments primarily focus on reducing inflammation and relapse rates rather than reversing neurological damage. Thus, one of the major therapeutic challenges is to develop strategies that can not only suppress the aberrant immune response but also enhance endogenous myelin regeneration and neurorepair, ultimately halting or even reversing disease progression. Recent studies have highlighted the critical role of chondroitin sulfate proteoglycans (CSPGs), a family of inhibitory extracellular matrix (ECM) molecules, in regulating CNS repair processes. CSPGs accumulate at the sites of demyelinated lesions and form a dense, inhibitory matrix that impedes the migration and differentiation of oligodendrocyte precursor cells (OPCs), thereby preventing effective myelin regeneration. CSPGs exert their inhibitory effects through several cell surface receptors, including leukocyte common antigen-related receptor (LAR), Nogo receptors (NgR1 and NgR3), and protein tyrosine phosphatase σ (PTPσ). Among these, PTPσ is a predominant receptor that mediates the biological activities of CSPGs via its phosphatase domains, which regulate downstream signaling pathways involved in cell proliferation, differentiation, and cytoskeletal organization. The CSPGs/PTPσ axis has been identified as a major molecular pathway contributing to the inhibition of remyelination in MS. The upregulation of CSPGs and PTPσ in MS lesions has been associated with a failure of OPCs to remyelinate damaged axons effectively. Preclinical studies have shown that pharmacological inhibition or genetic ablation of PTPσ can alleviate the inhibitory effects of CSPGs on OPC migration and differentiation. For instance, systemic administration of the PTPσ inhibiting peptide intracellular sigma peptide (ISP) has been shown to enhance OPC differentiation, promote remyelination, and restore motor function in animal models of MS, highlighting the potential of targeting CSPGs/PTPσ as a therapeutic approach for MS. Furthermore, CSPGs and their receptors have been implicated in modulating other biological processes such as immune cell infiltration, synaptic plasticity, and axonal regeneration, which are relevant to the pathogenesis of MS and other neurodegenerative diseases. CSPGs are known to activate downstream signaling pathways, such as the Rho/ROCK, Akt, and ERK pathways, which regulate cytoskeletal dynamics and gene expression in OPCs, ultimately affecting their ability to mature into myelinating oligodendrocytes. Additionally, CSPGs can interact with the N-cadherin/β-catenin pathway, influencing cell adhesion and signaling in OPCs, thereby modulating myelin repair capacity. Given the multifaceted roles of CSPGs/PTPσ in CNS pathology, targeting this pathway represents a promising therapeutic strategy. This article aims to provide a comprehensive overview of the biological properties of CSPGs and PTPσ, focusing on their roles in the inhibition of myelin regeneration. Specifically, it discusses how CSPGs/PTPσ signaling modulates various aspects of OPC biology, including autophagy regulation and immune modulation. Moreover, the review explores potential therapeutic strategies aimed at disrupting CSPGs/PTPσ interactions, such as the use of small-molecule inhibitors, neutralizing antibodies, or gene therapies. In summary, a deeper understanding of CSPGs/PTPσ-mediated signaling in OPCs and other cell types within MS lesions may reveal novel therapeutic targets for promoting remyelination and functional recovery. This review provides a detailed analysis of current findings and highlights the need for further research to translate these findings into effective treatments for MS patients.