Muscle fatigue has been studied for over a century, but almost no data are available to indicate how the brain perceives fatigue and modulates its signals to the fatiguing muscle. In this study, brain activation was measured by functional magnetic resonance imaging (fMRI) during a sustained (2-min) maximal-effort handgrip contraction while handgrip force and finger muscle electromyographic (EMG) data were recorded simultaneously by a magnetic resonance environment-adapted force-EMG measurement system. The results showed decoupled progresses in brain and muscle activities when muscle was fatigued and correlated behaviors among the cortical areas being analyzed. While handgrip force and EMG signals declined in parallel during the course of muscle fatigue, fMRI-measured brain activities first substantially increased and then decreased. This similar signal modulation occurred not only in the primary sensorimotor areas but also in the secondary and association cortices (supplementary motor, prefrontal, and cingulate areas). The nonlinear changes of brain signal may reflect an early adjustment to strengthen the descending command for force-loss compensation and subsequent inhibition by sensory feedback as fatigue became more severe. The close association in the activation pattern in many cortical regions may reflect integrated processing of information in the brain.