Deficits in cognitive abilities are commonly observed among individuals with multiple sclerosis (MS). Recent neuroimaging studies have provided evidence for the existence of cortical plasticity in MS, with cognitively impaired participants recruiting additional brain areas to perform challenging tasks. The existence of altered cerebral activations in MS provides hope for the utilization of neural resources to reduce cognitive deficits that challenge everyday living in MS by employing alternative interventions such as cognitive and fitness training. In this study, we examined whether higher physical fitness levels enhance cognitive and neural plasticity in MS patients. The present study is the first to investigate the impact of cardiorespiratory fitness on cerebrovascular functioning of MS patients. 24 participants with relapsing–remitting MS were recruited for the study. All participants went through a fitness assessment and were scanned in a 3 T MRI system during the Paced Visual Serial Addition Test (PVSAT). Higher fitness levels were associated with faster behavioral performance and greater recruitment of right IFG/MFG, a region of the cerebral cortex recruited by MS patients during performance of PVSAT to purportedly compensate for the cognitive deterioration attributable to MS. In contrast, lower levels of fitness were associated with enhanced ACC activity, suggestive of the presence of greater interference and the potential for error in lower fit MS participants. These results are promising, suggesting the need for further investigation of the utility of aerobic fitness training as a possible method to support the development of additional cortical resources in an attempt to counter the cognitive decline resulting from MS.