Cognitive fatigue (CF) is among the most common and disturbing aging symptoms, and substantially interferes with activities demanding sustained mental effort. Here we examined the relationship between the cortical-striatal network and CF (assessed by the 18-item visual analogue scale) when a group of cognitively and physically healthy older adults participated in a 30-minute cognitively fatiguing task-related fMRI experiment. We also explored whether CF would interfere with the “Posterior-Anterior Shifting in Aging” (PASA) phenomenon, an aging-associated neural reliance on frontal regions to support cognitive capacity. We revealed that decreased connectivity strength of the cortical-striatal network over the course of the task was related to higher CF. Correlation between CF and the cortical-striatal network was more robust in anterior relative to posterior components. Moreover, a positive relationship between reliance on the anterior part of the cortical-striatal network and cognitive performance only existed among older adults experiencing low CF. These findings suggest a crucial role of the cortical-striatal network, especially the anterior component, in linking to CF. The PASA phenomenon may only be applicable to older adults without vulnerability to CF.