A long history of research has revealed many neurophysiological changes and concomitant behavioral impacts of sleep deprivation, sleep restriction, and circadian rhythms. Little research, however, has been conducted in the area of computational cognitive modeling to understand the information processing mechanisms through which neurobehavioral factors operate to produce degradations in human performance. Our approach to understanding this relationship is to link predictions of overall cognitive functioning, or alertness, from existing biomathematical models to information processing parameters in a cognitive architecture, leveraging the strengths from each to develop a more comprehensive explanation. The integration of these methodologies is used to account for changes in human performance on a sustained attention task across 88 h of total sleep deprivation. The integrated model captures changes due to time awake and circadian rhythms, and it also provides an account for underlying changes in the cognitive processes that give rise to those effects. The results show the potential for developing mechanistic accounts of how fatigue impacts cognition, and they illustrate the increased explanatory power that is possible by combining theoretical insights from multiple methodologies.