Neoplastic, paraneoplastic, and hematologic disorders involving the central or peripheral nervous system may clinically and radiologically mimic multiple sclerosis (MS) and other inflammatory demyelinating diseases. This chapter reviews a broad spectrum of such conditions, including primary and secondary brain tumors (e.g., gliomas, CNS lymphomas), intramedullary spinal cord tumors (e.g., ependymomas, astrocytomas), histiocytic disorders (e.g., Erdheim–Chester disease, Langerhans cell histiocytosis), paraneoplastic neurologic syndromes (PNS), and autoimmune autonomic ganglionopathy. Each disorder is presented with a focus on epidemiology, pathogenesis, clinical features, neuroimaging findings, cerebrospinal fluid (CSF) profiles, and diagnostic challenges. Detailed imaging characteristics—such as enhancement patterns, lesion evolution, mass effect, and specific red flags like periventricular involvement or leptomeningeal spread—are discussed to aid in the differential diagnosis. Particular attention is paid to high-risk paraneoplastic antibodies and their associated malignancies and clinical phenotypes. Disorders such as glioblastoma or CNS lymphoma can mimic tumefactive MS, whereas paraneoplastic myelopathies may resemble neuromyelitis optica spectrum disorders. The chapter also covers diagnostic algorithms, including advanced MRI modalities, CSF analysis, flow cytometry, and molecular pathology. While some neoplastic and paraneoplastic syndromes require histologic confirmation via biopsy, others may be diagnosed through antibody profiling and clinical context. The timely identification of these mimics is critical, as immunotherapy may be harmful or ineffective in neoplastic processes and may delay necessary oncologic treatment. This chapter aims to provide clinicians with a practical and comprehensive guide to distinguishing neoplastic and paraneoplastic disorders from inflammatory demyelinating diseases.