Lack of sleep has a considerable impact on vigilance: we perform worse, we make more errors, particularly at night, when we should be sleeping. Measures of brain functional connectivity suggest that decrease in vigilance during sleep loss is associated with an impaired cross-talk within the fronto-parietal cortex. However, fronto-parietal effective connectivity, which is more closely related to the causal cross-talk between brain regions, remains unexplored during prolonged wakefulness. In addition, no study has simultaneously investigated brain effective connectivity and wake-related changes in vigilance, preventing the concurrent incorporation of the two aspects. Here, we used electroencephalography (EEG) to record responses evoked by Transcranial Magnetic Stimulation (TMS) applied over the frontal lobe in 23 healthy young men (18–30 yr.), while they simultaneously performed a vigilance task, during 8 sessions spread over 29 h of sustained wakefulness. We assessed Response Scattering (ReSc), an estimate of effective connectivity, as the propagation of TMS-evoked EEG responses over the fronto-parietal cortex. Results disclose a significant change in fronto-parietal ReSc with time spent awake. When focusing on the night-time period, when one should be sleeping, participants with lower fronto-parietal ReSc performed worse on the vigilance task. Conversely, no association was detected during the well-rested, daytime period. Night-time fronto-parietal ReSc also correlated with objective EEG measures of sleepiness and alertness. These changes were not accompanied by variations in fronto-parietal response complexity. These results suggest that decreased brain response propagation within the fronto-parietal cortex is associated to increased vigilance failure during night-time prolonged wakefulness. This study reveals a novel facet of the detrimental effect on brain function of extended night-time waking hours, which is increasingly common in our societies.