In times of digitalized workplaces the extent of challenging cognitive demands at work is rising and employees increasingly have to manage new and unlearned tasks. Yet, these work characteristics have received little attention on how they relate to the worker’s well-being. Thus, we analyze associations between cognitive work demands—also in interaction with other job characteristics—and indicators of employee well-being. The analyses are based on the BIBB/BAuA Employment Survey 2018, a cross-section that is representative for the German working population and covers approximately 20,000 employed individuals. Ordinary least squares (OLS) regressions suggest that cognitive demands are associated with a higher probability of feeling fatigued. In contrast, the results with respect to the employees’ self-rated health status and job satisfaction are ambiguous, depending on which cognitive demand is considered. Overall, the findings indicate that cognitive demands might be related to both resource and demand, depending on the individual resources of employees.