Fatigue stands among the most debilitating multiple sclerosis (MS) manifestations. Several pathophysiological mechanisms have been proposed at its origin. However, unmet needs still exist, and further investigations are required to better understand and manage this complaint. A new imaging modality—the phosphorous magnetic resonance spectroscopy ( 31 P-MRS)—might help studying fatigue by allowing the measurement of energy metabolites of various cerebral regions. Therefore, this work aimed to explore the association between fatigue and brain energy status. Thirty MS patients with progressive disease forms completed the study. Their sociodemographic and clinical data including fatigue and disability scores i.e., Fatigue Severity Scale (FSS) and Expanded Disability Status Scale (EDSS) were collected. 31 P-MRS spectra of (1) bilateral frontoparietal area and (2) centrum semiovale normal appearing white matter (NAWM) were obtained. Percentages of phosphocratine and β-adenosine triphosphate (β-ATP) were calculated. FSS scores were found to be directly correlated with the frontoparietal β-ATP % ( p  < 0.05). However, there were no significant correlations between FSS scores and NAWM energy metabolites or clinical data (i.e., age, EDSS scores or disease duration). These findings point toward the existence of a link between fatigue severity and the amount of cerebral ATP metabolites. Such a link might reflect either a high production or low utilization of ATP, both of which were paralleled with increased fatigue perception. While the former would be due to a redistribution of ion channels along demyelinated axons and subsequent changes in mitochondrial activity; the latter could be interpreted in the light of neuronal loss which would lead to a decrease in ATP utilization and accumulation of its metabolites.