Multiple sclerosis (MS) and myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) share the symptom of fatigue, and might even coexist together. Specifically focusing on genetics, pathophysiology, and neuroimaging data, the authors discuss an overview of the parallels, correlation, and differences in fatigue between MS and ME/CFS along with ME/CFS presence in MS. Studies have revealed that the prefrontal cortex and basal ganglia regions, which are involved in fatigue regulation, have similar neuroimaging findings in the brains of people with both MS and ME/CFS. Additionally, in both conditions, genetic factors have been implicated, with particular genes known to enhance susceptibility to MS and CFS. Management approaches for fatigue in MS and ME/CFS differ based on the underlying factors contributing to fatigue. The authors also focus on the recent updates and the relationship between MS and sleep disorders, including restless legs syndrome, focusing on pathophysiology and therapeutic approaches. Latest therapeutic approaches like supervised physical activity and moderate-intensity exercises have shown better outcomes.