Driving fatigue is a serious issue for the transportation sector, decreasing the driver�s performance and increasing accident risk. This study aims to investigate how fatigue mediates the relationship between the nature of work factors and driving performance. The approach included a review of the previous studies to select the dimensional items for the data collection instrument. A pilot test to identify potential modification to the questionnaire was conducted, then structural equation modelling (SEM) was performed on a stratified sample of 307 drivers, to test the suggested hypotheses. Based on the results, five hypotheses have indirect relationships, four of which have a significant effect. Besides, the results show that driving fatigue partially mediates the relationship between the work schedule and driving performance and fully mediates in the relationship between work activities and driving performance. The nature of work and human factors is the most common reason related to road accidents. Therefore, the emphasis on driving performance and fatigue factors would thereby lead to preventing fatal crashes and life loss. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.