Intensive care nurses are highly prone to occupational stress and burnout, affecting their physical and mental health. The occurrence of the pandemic and related events increased nurses’ workload and exacerbated stress and burnout. We conducted a prospective longitudinal mixed-methods study with a cohort of nurses working in a medical ICU (COVID unit; n = 14) and cardiovascular ICU (non-COVID unit; n = 5). Each participant was followed for six 12-hour shifts. Validated questionnaires measured occupational stress and burnout prevalence. Wrist-worn wearable technologies recorded physiological indices of stress. Participants elaborated on the contributors to stress via post-study questionnaire. Data were analyzed using statistical and qualitative methods. Participants who cared for COVID patients at the COVID unit were 3.71 times more likely to experience stress (p < .001) in comparison to non-COVID unit participants. No differences in stress levels were found when the same participants worked with COVID and non-COVID patients at different shifts at the COVID unit. The cohorts expressed similar contributors to stress including communication tasks, patient acuity, clinical procedures, admission processes, proning, labs, and assisting coworkers. Nurses in COVID units, irrespective of whether they care for a COVID patient, may experience high occupational stress and burnout.