Neurocognitive mechanisms underlying the effects of mental fatigue are poorly understood. Here, we examined whether error-related brain activity, indexing performance monitoring by the anterior cingulate cortex (ACC), and strategic behavioural adjustments were modulated by mental fatigue, as induced by 2 h of continuous demanding cognitive task performance. Findings that (1) mental fatigue is associated with compromised performance monitoring and inadequate performance adjustments after errors, (2) monitoring functions of ACC and striatum rely on dopaminergic inputs from the midbrain, and (3) patients with striatal dopamine deficiencies show symptomatic mental fatigue, suggest that mental fatigue results from a failure to maintain adequate levels of dopaminergic transmission to the striatum and the ACC, resulting in impaired cognitive control.