Multiple sclerosis patients frequently receive diagnoses for fatigue and Melancholy (MS). The subjective lack of physical and/ or mental energy known as fatigue is present in 35%-97% of MS patients, who list it as one of the most severe symptoms affecting everyday activities and quality of life. 50 percent of MS patients have depression, according to diagnosis. Since melancholy and fatigue frequently coexist, it might be challenging to tell the two apart. In MS, inflammatory, oxidative/nitrosative, and neurodegenerative processes that cause demyelination, axonal damage, and brain atrophy are the main causes of primary fatigue and primary depression. The concentration of inflammatory mediators like tumour necrosis factor, interleukins (IL-1a, IL-1b, and IL-6), interferon, and neopterin is found to be higher in the serum and cerebrospinal fluid of MS patients who also have comorbid fatigue and/or depression. In addition, prefrontal, frontal, parietotemporal, thalamic, and basal ganglia atrophy were seen in MS patients who also experienced fatigue and/or melancholy. People with MS may experience secondary fatigue and secondary depression due to emotional factors, sleep issues, pain, the coexistence of other illnesses, and medication use. In some studies, the use of disease modifying therapies had a beneficial impact on fatigue, likely by reducing the inflammatory response, demonstrating how closely immunological factors relate to both fatigue and depression.