© 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group. Objective: The Accreditation Council for Graduate Medical Examination recently revised and implemented duty hour standards that increased maximum duty hours for first-year medical residents and reduced the minimal amount of time off between duty periods for all medical residents. Little work has examined driving performance of medical residents at multiple periods surrounding duty, including in reference to off-duty driving performance as a baseline. Certain work-related factors that may be negatively impacted in medical residents, such as sleep quality, fatigue, and stress, are known to affect mental and physical performance and may further exacerbate driving risks. The overall objective of this study was to examine driving performance of medical residents off duty, preduty, and postduty using a high-fidelity driving simulator. Method: Thirty-two medical residents were enrolled and wore sleep tracking devices over several days. Both self-reported and objective estimates of sleep quality, fatigue, and stress were collected at off-duty, preduty, and postduty points of time. The medical residents drove in a high-fidelity driving simulator at each time point to provide objective driving performance metrics. Results: Findings indicated that medical residents experienced the highest levels of stress and sleep propensity preduty and displayed riskier driving behaviors postduty. Those further into their residency were less affected by the negative effect of stress on driving performance, and those with better sleep quality metrics were also less affected by the negative effects of increased stress on driving outcomes. Conclusions: The impact of occupational demands on psychophysiological outcomes requires further investigation to better understand the mechanisms of how work demands affect these psychophysiological outcomes. Understanding how to mitigate high job strain may have several implications in improving psychophysiological functions impacted by occupational demands, namely, sleep quality and stress, and subsequently improving driving safety outcomes that may also be negatively affected by the duty demands.