Objective: This study investigates the combined effect of the Effort/Reward Imbalance (ERI) model of stress and work intensification within the context of the COVID-19 pandemic on the psychological health (general and work-related fatigue, and psychological strain) of cargo drivers, one of the most demanded workforces during the first year of this pandemic. Methods: For this cross-sectional research, the data provided by n = 1,013 professional drivers from the different 17 autonomous communities (regions) of Spain were analyzed. Participants answered a questionnaire composed of the short version of the Effort Reward Imbalance (ERI) questionnaire, a Work Intensification Scale (WIS) designed for this study, the fatigue subscale of the Checklist Individual Strength (CIS), the Need for Recovery after Work Scale (NFR), and the General Health Questionnaire (GHQ). Results: Hierarchical regression analyses show that both (ERI and work intensification) models significantly predict driver's fatigue and psychological strain. The effect of work intensification exists above and beyond the effect of effort/reward imbalance, which has been previously related to the safety performance of cargo drivers. Conclusions: These findings suggest that the ERI and work intensification models can be complementarily used, especially in scenarios introducing substantial changes in the work environment, such as the COVID-19 crisis. Also, the results of this study support the need to intervene in the working conditions of professional drivers in order to improve their psychological health and well-being during both pandemic and post-pandemic times, as crisis-related management interventions are necessary