Introduction: Recent evidence consistently highlights the adverse work environment of long-haul professional drivers, whose task structure typically involves the performance of extensive shifts, driving under stressful working conditions. In this regard, job stress and fatigue – that are highly prevalent in this workforce – seem to play a crucial role in explaining this group’s negative traffic safety outcomes. The aim of this study was to assess whether work-related fatigue is a mechanism that mediates the relationship between job stress, health indicators and occupational traffic crashes of long-haul truck drivers (LHTD). Methods: The data used in this study were collected from 521 Spanish long-haul truck drivers (97% males) from all 17 regions of Spain, with a mean age of 47 years. Results: Utilizing structural equation models (SEM), it was found that work-traffic crashes of long-haul truck drivers could be explained through work-related fatigue that exerts a full mediation between job stress (job strain), health-related factors and traffic crashes suffered during the previous two years. Discussion: Overall, the findings of this research support that a) stressful working conditions and health issues of drivers have significant effects on traffic crashes, and b) fatigue is a mechanism relating stress-related factors and work-traffic crashes of long-haul drivers. This study highlights the need of stress- and fatigue-management policies and interventions, in order to reduce the crash risk of long-haul truck drivers.